Imidazopyridines pyrimidines and triazines for enhancing cognition as gaba-a-alphas 5 receoptor subtype ligands

ABSTRACT

The present invention provides a pharmaceutical composition providing a compound of formula I or a pharmaceutically acceptable salt thereof in a pharmaceutically acceptable excipient: (I), in which: X and Y independently represent CH or N, with the proviso that if X is CH then Y is also CH; R 1  represents hydrogen, hydrocarbon, a heterocyclic group, halogen, cyano, trifluoromethyl, nitro, —OR a , —SR a , —SOR a , —SO 2 R a , —SO 2 NR a R b , —NR a R b , —NR a COR b , —NR a CO 2 R b , —COR a , —CO 2 R a , —CONR a R b  or CR a ═NOR b ; R a  and R b  independently represent hydrogen, hydrocarbon or a heterocyclic group; V and W are independently selected from H, halogen, C 11-6 alkyl, OH and C -1-6 alkoxy; Z represents H, halogen, CN, NO 2 , CF 3 , OCF 3 , CF 2 H, SCF 3 , R 2 , OR 3 , SR 3 , (CH 2 )pN(R 3 ) 2 , O(CH 2 )pN(R 3 ) 2 , SO 2 R 2 , SO 2 N(R 3 ) 2 , COR 4 , CO 2 R 3 , CON(R 3 ) 2 , NHCOR 4 , NR 1 (CH 2 ) n heteroaryl or O(CH 2 ) n heteroaryl the heteroaryl is optionally substituted by one, two or three groups chosen from C 1-6 alkyl, benzyl, (CH 2 )pN(R 3 ) 2 , halogen and CF 3 , R 1  is C 1-6 alkyl, where n is 1 or 2 and p is 0, 1 or 2; with the proviso that at least one of V, W and Z is other than H; R 2  represents C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkylC 1-4 alkyl, C 2-6 alkenyl, C 2-6 alkynyl or heteroaryl, any of which may bear a substituent selected from halogen, CN, NO 2 , CF 3 , OCF 3 , CF 2 H, SCF 3 , OH, C 1-4 alkoxy, C 1-4 alkoxycarbonyl, amino, C 1-4 alkylamino, or di(C 1-4 alkyl)amino; R 3  represents H or R 2 ; or two R 3  groups bonded to the same nitrogen atom may complete a 5-7 membered nonaromatic heterocyclic ring; and R 4  represents R 3  or heteroaryl; the compounds are ligands for GABA-A receptors containing the alpha 5 subtype and thus are useful for enhancing cognition in individuals suffering from conditions such as Alzheimer&#39;s Disease.

The present invention relates to a class of substituted fused imidazolederivatives and to their use in therapy. More particularly, thisinvention is concerned with substituted imidazo[1,2-a]pyrimidine,imidazo[1,2-b][1,2,4]triazine and imidazo[1,2-a]pyridine derivativeswhich are ligands for GABA_(A) receptors containing the α5 subunit andare therefore useful in therapy where cognition enhancement is required.

Receptors for the major inhibitory neurotransmitter, gamma-aminobutyricacid (GABA), are divided into two main classes: (1) GABA_(A) receptors,which are members of the ligand-gated ion channel superfamily; and (2)GABA_(B) receptors, which may be members of the G-protein linkedreceptor superfamily. Since the first cDNAs encoding individual GABA_(A)receptor subunits were cloned, the number of known members of themammalian family has grown to include at least six a subunits, four βsubunits, three γ subunits, one δ subunit, one ε subunit and two ρsubunits.

Although knowledge of the diversity of the GABA_(A) receptor gene familyrepresents a huge step forward in our understanding of this ligand-gatedion channel, insight into the extent of subtype diversity is still at anearly stage. It has been indicated that an α subunit, a β subunit and aγ subunit constitute the minimum requirement for forming a fullyfunctional GABA_(A) receptor expressed by transiently transfecting cDNAsinto cells. As indicated above, δ, ε and ρ subunits also exist, but arepresent only to a minor extent in GABA_(A) receptor populations.

Studies of receptor size and visualisation by electron microscopyconclude that, like other members of the ligand-gated ion channelfamily, the native GABA_(A) receptor exists in pentameric form. Theselection of at least one α, one β and one γ subunit from a repertoireof seventeen allows for the possible existence of more than 10,000pentameric subunit combinations. Moreover, this calculation overlooksthe additional permutations that would be possible if the arrangement ofsubunits around the ion channel had no constraints (i.e. there could be120 possible variants for a receptor composed of five differentsubunits).

Receptor subtype assemblies which do exist include α1β2γ2, α2β2/3γ2,α3βγ2/3, α2βγ1, α5β3γ2/3, α6βγ2, α6βδ and 60 4βδ. Subtype assembliescontaining an α1 subunit are present in most areas of the brain andaccount for over 40% of GABA_(A) receptors in the rat. Subtypeassemblies containing α2 and α3 subunits respectively account for about25% and 17% of GABA_(A) receptors in the rat. Subtype assembliescontaining an α5 subunit are expressed predominantly in the hippocampusand cortex and are thought to represent about 4% of receptors in therat.

A characteristic property of all known GABA_(A) receptors is thepresence of a number of modulatory sites, one of which is thebenzodiazepine (BZ) binding site. The BZ binding site is the mostexplored of the GABA_(A) receptor modulatory sites, and is the sitethrough which anxiolytic drugs such as diazepam and temazepam exerttheir effect. Before the cloning of the GABA_(A) receptor gene family,the benzodiazepine binding site was historically subdivided into twosubtypes, BZ1 and BZ2, on the basis of radioligand binding studies. TheBZ1 subtype has been shown to be pharmacologically equivalent to aGABA_(A) receptor comprising the α1 subunit in combination with β2 andγ2. This is the most abundant GABA_(A) receptor subtype, representingalmost half of all GABA_(A) receptors in the brain.

A number of dementing illnesses such as Alzheimer's disease arecharacterised by a progressive deterioration in cognition in thesufferer. It would clearly be desirable to enhance cognition in subjectsdesirous of such treatment, for example for subjects suffering from adementing illness.

It has been reported by McNamara and Skelton in Psychobiology,21:101-108, that the benzodiazepine receptor inverse agonist β-CCMenhanced spatial learning in the Morris watermaze. However, β-CCM andother conventional benzodiazepine receptor inverse agonists areproconvulsant which makes it clear that they cannot be used as cognitionenhancing agents in humans.

However, we have now discovered that it is possible to obtainmedicaments which have cognition enhancing effects which may be employedwith less risk of proconvulsant effects previously described withbenzodiazepine receptor partial or full inverse agonists.

It has now been discovered that use of an α5 receptor partial or fullinverse agonist which is relatively free of activity at α1 and/or α2and/or α3 receptor binding sites can be used to provide a medicamentwhich is useful for enhancing cognition but in which proconvulsantactivity is reduced or eliminated. Inverse agonists at α5 which are notfree of activity at α1 and/or α2 and/or α3 but which are functionallyselective for α5 can also be used. Inverse agonists which are bothselective for α5 and are relatively free of activity at α1, α2 and α3receptor binding sites are preferred.

International Patent Publication No. WO01/038326 discloses certain3-phenylimidazo[1,2-a]pyridines to be ligands for GABA_(A) receptors,but neither discloses nor suggests compounds in accordance with thepresent invention.

According to the invention there is provided a pharmaceuticalcomposition comprising, in a pharmaceutically acceptable carrier, one ormore compounds of formula I or pharmaceutically-acceptable saltsthereof:

wherein:

X and Y independently represent CH or N, with the proviso that if X isCH then Y is also CH;

R¹ represents hydrogen, hydrocarbon, a heterocyclic group, halogen,cyano, trifluoromethyl, nitro, —OR^(a), —SR^(a), —SOR^(a), —SO₂R^(a),—SO₂NR^(a)R^(b), —NR^(a)R^(b), —NR^(a)COR^(b), —NR^(a)CO₂R^(b),—COR^(a), —CO₂R^(a), —CONR^(a)R^(b) or —CR^(a)═NOR^(b);

R^(a) and R^(b) independently represent hydrogen, hydrocarbon or aheterocyclic group;

V and W are independently selected from H, halogen, C₁₋₆alkyl, OH andC₁₋₆alkoxy;

Z represents H, halogen, CN, NO₂, CF₃, OCF₃, CF₂H, SCF₃, R², OR³, SR³,(CH₂)_(p)N(R³)₂, O(CH₂)_(p)N(R³)₂, SO₂R², SO₂N(R³)₂, COR⁴, CO₂R³,CON(R³)₂, NHCOR⁴, NR′(CH₂)_(n)heteroaryl or O(CH₂)_(n)heteroaryl wherethe heteroaryl is optionally substituted by one, two or three groupschosen from C₁₋₆alkyl, benzyl, (CH₂)_(p)N(R³)₂, halogen and CF₃, R′ isC₁₋₆alkyl, n is 1 or 2 and p is 0, 1 or 2;

with the proviso that at least one of V, W and Z is other than H;

R² represents C₁₋₆alkyl, C₃₋₆cycloalkyl, C₃₋₆cycloalkylC₁₋₄alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl or heteroaryl, any of which may bear asubstituent selected from halogen, CN, NO₂, CF₃, OCF₃, CF₂H, SCF₃, OH,C₁₋₄alkoxy, C₁₋₄alkoxycarbonyl, amino, C₁₋₄alkylamino, ordi(C₁₋₄alkyl)amino;

R³ represents H or R²; or two R³ groups bonded to the same nitrogen atommay complete a 5-7 membered nonaromatic heterocyclic ring; and

R⁴ represents R³ or heteroaryl.

In a subset of the compounds of formula I, X represents N and Yrepresents N or CH.

In a second aspect, the invention provides a compound of formula I asdefined above, or a pharmaceutically acceptable salt thereof, for use intreatment of the human body. Preferably the treatment is for a conditionassociated with GABA_(A) receptors comprising the α5 subunit and/or forthe enhancement of cognition. Preferably the condition is a neurologicaldeficit with an associated cognitive disorder such as a dementingillness such as Alzheimer's disease. Other conditions to be treatedinclude cognition deficits due to traumatic injury, stroke, Parkinson'sdisease, Downs syndrome, age related memory deficits, attention deficitdisorder and the like.

The present invention further provides the use of a compound of formulaI as defined above, or a pharmaceutically acceptable salt thereof, inthe manufacture of a medicament for the enhancement of cognition,preferably in a human suffering from a dementing illness such asAlzheimer's disease.

Also disclosed is a method of treatment of a subject suffering from acognition deficit, such as that resulting from a dementing illness suchas Alzheimer's disease, which comprises administering to that subject aneffective amount of a compound according to the present invention.

In a further aspect, the present invention provides a compound offormula I as defined above, or a pharmaceutically acceptable saltthereof, with the proviso that Z is other than halogen, OH, OCH₃ or NH₂.

For use in medicine, the salts of the compounds of formula I will bepharmaceutically acceptable salts. Other salts may, however, be usefulin the preparation of the compounds according to the invention or oftheir pharmaceutically acceptable salts. Suitable pharmaceuticallyacceptable salts of the compounds of this invention include acidaddition salts which may, for example, be formed by mixing a solution ofthe compound according to the invention with a solution of apharmaceutically acceptable acid such as hydrochloric acid, sulphuricacid, methanesulphonic acid, fumaric acid, maleic acid, succinic acid,acetic acid, benzoic acid, oxalic acid, citric acid, tartaric acid,carbonic acid or phosphoric acid. Furthermore, where the compounds ofthe invention carry an acidic moiety, suitable pharmaceuticallyacceptable salts thereof may include alkali metal salts, e.g. sodium orpotassium salts; alkaline earth metal salts, e.g. calcium or magnesiumsalts; and salts formed with suitable organic ligands, e.g. quaternaryammonium salts.

The term “hydrocarbon” as used herein includes straight-chained,branched and cyclic groups containing up to 18 carbon atoms, suitably upto 15 carbon atoms, and conveniently up to 12 carbon atoms. Suitablehydrocarbon groups include C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇cycloalkyl, C₃₋₇ cycloalkyl(C₁₋₆)alkyl, indanyl, aryl andaryl(C₁₋₆)alkyl.

The expression “a heterocyclic group” as used herein includes cyclicgroups containing up to 18 carbon atoms and at least one heteroatompreferably selected from oxygen, nitrogen and sulphur. The heterocyclicgroup suitably contains up to 15 carbon atoms and conveniently up to 12carbon atoms, and is preferably linked through carbon. Examples ofsuitable heterocyclic groups include C₃₋₇ heterocycloalkyl, C₃₋₇heterocycloalkyl(C₁₋₆)alkyl, heteroaryl and heteroaryl(C₁₋₆)alkylgroups.

Suitable alkyl groups include straight-chained and branched alkyl groupscontaining from 1 to 6 carbon atoms. Typical examples include methyl andethyl groups, and straight-chained or branched propyl, butyl and pentylgroups. Particular alkyl groups are methyl, ethyl, n-propyl, isopropyl,isobutyl, tert-butyl and 2,2-dimethylpropyl. Derived expressions such as“C₁₋₆ alkoxy”, “C₁₋₆ alkylamino” and “C₁₋₆ alkylsulphonyl” are to beconstrued accordingly.

Suitable alkenyl groups include straight-chained and branched alkenylgroups containing from 2 to 6 carbon atoms. Typical examples includevinyl, allyl and dimethylallyl groups.

Suitable alkynyl groups include straight-chained and branched alkynylgroups containing from 2 to 6 carbon atoms. Typical examples includeethynyl and propargyl groups.

Suitable cycloalkyl groups include groups containing from 3 to 7 carbonatoms. Particular cycloalkyl groups are cyclopropyl and cyclohexyl.

Typical examples of C₃₋₇ cycloalkyl(C₁₋₆)alkyl groups includecyclopropylmethyl, cyclohexylmethyl and cyclohexylethyl.

Particular indanyl groups include indan-1-yl and indan-2-yl.

Particular aryl groups include phenyl and naphthyl, preferably phenyl.

Particular aryl(C₁₋₆)alkyl groups include benzyl, phenylethyl,phenylpropyl and naphthylmethyl.

Suitable heterocycloalkyl groups include azetidinyl, pyrrolidinyl,piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl groups.

A typical C₃₋₇ heterocycloalkyl(C₁₋₆)alkyl group is morpholinylmethyl.

Suitable heteroaryl groups include pyridinyl, quinolinyl, isoquinolinyl,pyridazinyl, pyrimidinyl, pyrazinyl, furyl, benzofuryl, dibenzofuryl,thienyl, benzthienyl, pyrrolyl, indolyl, pyrazolyl, indazolyl, oxazolyl,isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, benzimidazolyl,oxadiazolyl, thiadiazolyl, triazolyl and tetrazolyl groups.

The expression “heteroaryl(C₁₋₆)alkyl” as used herein includesfurylmethyl, furylethyl, thienylmethyl, thienylethyl, oxazolylmethyl,oxazolylethyl, thiazolylmethyl, thiazolylethyl, imidazolylmethyl,imidazolylethyl, pyrazolylmethyl, pyrazolylethyl, oxadiazolylmethyl,oxadiazolylethyl, thiadiazolylmethyl, thiadiazolylethyl,triazolylmethyl, triazolylethyl, tetrazolylmethyl, tetrazolylethyl,pyridinylmethyl, pyridinylethyl, pyrimidinylmethyl, pyrazinylmethyl,quinolinylmethyl and isoquinolinylmethyl.

The hydrocarbon and heterocyclic groups may in turn be optionallysubstituted by one or more groups selected from C₁₋₆ alkyl, adamantyl,phenyl, halogen, C₁₋₆haloalkyl, C₁₋₆aminoalkyl, trifluoromethyl,hydroxy, C₁₋₆alkoxy, aryloxy, keto, C₁₋₃alkylenedioxy, nitro, cyano,carboxy, C₁₋₆alkoxycarbonyl, C₁₋₆alkoxycarbonyl(C₁₋₆)alkyl,C₁₋₆alkylcarbonyloxy, arylcarbonyloxy, aminocarbonyloxy,C₁₋₆alkylcarbonyl, arylcarbonyl, C₁₋₆ alkylthio, C₁₋₆ alkylsulphinyl,C₁₋₆ alkylsulphonyl, arylsulphonyl, —NR^(v)R^(w), —NR^(v)COR^(w),—NR^(v)CO₂R^(w), —NR^(v)SO₂R^(w), —CH₂NR^(v)SO₂R^(w), —NHCONR^(v)R^(w),—CONR^(v)R^(w), —SO₂NR^(v)R^(w) and —CH₂SO₂NR^(v)R^(w), in which R^(v)and R^(w) independently represent hydrogen, C₁₋₆alkyl, aryl oraryl(C₁₋₆)alkyl.

The term “halogen” as used herein includes fluorine, chlorine, bromineand iodine, especially fluoro or chloro.

Where the compounds according to the invention have at least oneasymmetric centre, they may accordingly exist as enantiomers. Where thecompounds according to the invention possess two or more asymmetriccentres, they may additionally exist as diastereoisomers. It is to beunderstood that all such isomers and mixtures thereof in any proportionare encompassed within the scope of the present invention.

Typically, R¹ represents hydrogen, hydrocarbon, a heterocyclic group,halogen, cyano, trifluoromethyl, —OR^(a), —COR^(a), —CO₂R^(a),—CONR^(a)R^(b) or —CR^(a)═NOR^(b). Suitably, R¹ represents hydrocarbon,a heterocyclic group, cyano, halogen, trifluoromethyl, —OR^(a),—COR^(a), —CO₂R^(a), —CONR^(a)R^(b) or —CR^(a)═NOR^(b).

Typical values of R^(a) include hydrogen and C₁₋₆ alkyl. Suitably, R^(a)represents hydrogen or methyl.

Typical values of R^(b) include hydrogen, C₁₋₆ alkyl, hydroxy(C₁₋₆)alkyland di(C₁₋₆)alkylamino(C₁₋₆)alkyl. Suitably, R^(b) represents hydrogen,methyl, ethyl, hydroxyethyl or dimethylaminoethyl. Particular values ofR^(b) include hydrogen, hydroxyethyl and dimethylaminoethyl, especiallyhydrogen or dimethylaminoethyl.

Representative values of R¹ include hydrogen, C₁₋₆ alkyl,halo(C₁₋₆)alkyl, dihalo(C₁₋₆)alkyl, hydroxy(C₁₋₆)alkyl, C₁₋₆alkoxy(C₁₋₆)alkyl, di(C₁₋₆)alkoxy(C₁₋₆)alkyl, C₃₋₇ cycloalkyl, C₃₋₇heterocycloalkyl(C₁₋₆)alkyl, heteroaryl, C₁₋₆ alkyl-heteroaryl,heteroaryl(C₁₋₆)alkyl, halogen, cyano, trifluoromethyl, C₁₋₆ alkoxy,formyl, C₁₋₆alkylcarbonyl, C₁₋₆alkoxycarbonyl, —CONR^(a)R^(b) and—CR^(a)═NOR^(b), in which R^(a) and R^(b) are as defined above.

Illustrative values of R¹ include C₁₋₆ alkyl, hydroxy(C₁₋₆)alkyl,heteroaryl, halogen, cyano, trifluoromethyl, C₁₋₆ alkoxy, formyl,C₁₋₆alkylcarbonyl, C₁₋₆alkoxycarbonyl, —CO₂H, —CONR^(a)R^(b) and—CR^(a)═NOR^(b), in which R^(a) and R^(b) are as defined above.

Itemised values of R¹ include hydrogen, methyl, fluoromethyl,difluoromethyl, hydroxymethyl, methoxymethyl, dimethoxymethyl,hydroxyethyl (especially 1-hydroxyethyl), fluoroethyl (especially1-fluoroethyl), difluoroethyl (especially 1,1-difluoroethyl),dimethoxyethyl (especially 1,1-dimethoxyethyl), isopropyl, hydroxypropyl(especially 2-hydroxyprop-2-yl), fluoropropyl (especially2-fluoroprop-2-yl), tert-butyl, cyclopropyl, cyclobutyl,morpholinylmethyl, pyridinyl, furyl, thienyl, oxazolyl, isoxazolyl,methylisoxazolyl, methylthiazolyl, methyloxadiazolyl, imidazolylmethyl,triazolylmethyl, chloro, cyano, trifluoromethyl, methoxy, formyl,acetyl, methoxycarbonyl, —CO₂H, carbamoyl and —CR^(aa)═NOR^(bb), inwhich R^(aa) represents hydrogen or methyl, and R^(bb) representshydrogen, hydroxyethyl or dimethylaminoethyl.

Selected values of R¹ include hydrogen, methyl, fluoromethyl,difluoromethyl, hydroxymethyl, dimethoxymethyl, dimethoxyethyl(especially 1,1-dimethoxyethyl), isopropyl, hydroxypropyl (especially2-hydroxyprop-2-yl), tert-butyl, cyclopropyl, cyclobutyl,morpholinylmethyl, methylisoxazolyl, cyano, chloro, trifluoromethyl,methoxy, formyl, acetyl, methoxycarbonyl, carbamoyl, —CO₂H and—CR^(aa)═NOR^(bb), in which R^(aa) and R^(bb) are as defined above.

Specific values of R¹ include cyano, chloro, trifluoromethyl, formyl,—CO₂H, methoxycarbonyl, carbamoyl, —CH═NOH and 5-methylisoxazol-3-yl.

In one favoured embodiment, R¹ represents trifluoromethyl.

In a particular embodiment, V, Z and W occupy the 2-, 3- and 4-positionsrespectively of the phenyl ring.

Typically, V and W independently represent H, halogen (especially Cl orF) or C₁₋₆alkyl (such as methyl, ethyl, n-propyl or isopropyl,especially methyl). In a particular embodiment, V represents H, Cl or Fand W represents H, Cl, F or methyl, and typically at least one of V andW represents H.

In one embodiment Z represents H, halogen, CN, NO₂, CF₃, OCF₃, CF₂H,SCF₃, R², OR³, SR³, N(R³)₂, SO₂R², SO₂N(R³)₂, COR⁴, CO₂R³, CON(R³)₂,NHCOR⁴, NH(CH₂)_(n)heteroaryl or O(CH₂)_(n)heteroaryl where n is 1 or 2.

Z represents H, halogen, CN, NO₂, CF₃, OCF₃, CF₂H, SCF₃, R², OR³, SR³,N(R³)₂, SO₂R², SO₂N(R³)₂, COR⁴, CO ₂R³, CON(R³)₂, NHCO⁴,NH(CH₂)_(n)heteroaryl or O(CH₂)_(n)heteroaryl where n is 1 or 2, whereR², R³ and R⁴ are as previously defined.

At least one of V, Z and W is other than H.

In one embodiment R² represents R² represents C₁₋₆alkyl, C₃₋₆cycloalkyl,C₃₋₆cycloalkylC₁₋₄alkyl, C₂₋₆alkenyl or C₂₋₆alkynyl, any of which maybear a substituent selected from halogen, CN, NO₂, CF₃, OCF₃, CF₂H,SCF₃, OH, C₁₋₄alkoxy, C₁₋₄alkoxycarbonyl, amino, C₁₋₄alkylamino, ordi(C₁₋₄alkyl)amino.

R² preferably represents C₁₋₆alkyl, such as methyl, ethyl, n-propyl,isopropyl, n-butyl or t-butyl, optionally substituted as definedpreviously. Typical substituents include halogen, hydroxy and methoxy.Preferably, alkyl groups represented by R² are unsubstituted orsubstituted with methoxy.

R³ represents H or R², or two R³ groups bonded to the same nitrogen atomcan complete a 5-7 membered nonaromatic heterocycle. Examples of suchN(R³)₂ groups include pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl,morpholin-4-yl and thiomorpholin-4-yl.

R⁴ represents R³ or heteroaryl. Examples of heteroaryl groupsrepresented by R⁴ include pyridyl, especially 3-pyridyl.

When Z represents —NH(CH₂)_(n)heteroaryl or —O(CH₂)_(n)heteroaryl, n ispreferably 1, and the heteroaryl moiety is preferably pyridyl,especially 3-pyridyl, or is a 5-membered ring, such as pyrazole,imidazole, triazole and substituted derivatives thereof. Preferredsubstituents include alkyl (especially methyl) and trifluoromethyl.

Examples of groups represented by Z therefore include H, halogen(especially Br, Cl and F), CN, NO₂, CF₃, OCF₃, CF₂H, SCF₃, amino,t-butylamino, dimethylamino, morpholin-4-yl, methyl, methoxymethyl,isopropyl, methoxy, methylthio, acetamido, N,N-dimethylcarbamoyl,methanesulphonyl, N,N-dimethylaminosulphonyl, 3-pyridylcarbonyl,(3-pyridylmethyl)amino, (1,5-dimethylpyrazol-4-ylmethyl)amino,(1-methyl-5-trifluoromethylpyrazol-4-ylmethyl)amino,(2-methyl-[1,2,4]triazol-3-yl)methoxy,(1-methyl-[1,2,4]triazol-3-yl)methoxy and(1,5-dimethylpyrazol-4-yl)methoxy. Further specific examples of Zinclude CHO, morpholin-4-ylmethyl, N-t-butylaminomethyl, acetyl,N,N-dimethylaminomethyl, pyrid-2-ylmethoxy, pyrid-3-ylmethoxy,1-methyl-[1,2,3,]triazol-4-ylmethoxy, pyrid-4-ylmethoxy,5-t-butyl-[1,2,4]oxadiazol-3-ylmethoxy,1-methyl-[1,2,4]triazol-5-ylmethylamino,2-methyl-[1,2,4]triazol-5-ylmethylamino,3,5-dimethylisoxazol-4-ylmethoxy, 5-methylisoxazol-3-ylmethoxy,morpholin-4-ylethoxy, OCH₂CN, 2-methylthiazol-4-ylmethoxy,1-ethyl-[1,2,4]triazol-5-ylmethoxy,1-isopropyl-[1,2,4]triazol-5-ylmethoxy,1-methyl-5-chloro-3-trifluoromethylpyrazol-4-ylmethoxy,1,5-dimethylpyrazol-3-ylmethoxy, 1,3-dimethylpyrazol-5-ylmethoxy,1-methyl-5-chloropyrazol-4-ylmethoxy, ethoxy, 2,2,2-trifluoroethoxy,1-methylimidazol-2-ylmethoxy, 1-methyltetrazol-5-ylmethoxy,pyrazin-2-ylmethoxy, pyrid-4-ylmethoxy, pyrimidin-6-ylmethoxy,2-chlorothien-5-ylmethoxy, isopropoxy, 1-benzylimidazol-2-ylmethoxy,fur-2ylmethoxy, fur-3-ylmethoxy, thien-3-ylmethoxy,isoxazol-3-ylmethoxy, isoxazol-5-ylmethoxy, isoxazol-4-ylmethoxy,pyrimidin-5-ylmethoxy, oxazol-5-ylmethoxy,1-dimethylaminoethyl-[1,2,4]triazin-5-ylmethoxy,1-methylimidazol-5-ylmethoxy, 1-methylpyrazol-3-ylmethoxy,1-methylpyrazol-5-ylmethoxy, 3-methylisothiazol-5-ylmethoxy,thien-2-ylmethoxy, 1-methyl-[1,2,3]triazol;-4-ylmethylamino,thiazol-4-ylmethoxy, N-methyl-N-1-methyl-[1,2,3]triazol-4-ylmethylamino,isoxazol-5-ylmethylamino, pyrid-3-ylethoxy, pyrid-4-ylethoxy,4-methylthiazol-5-ylethoxy, OCH₂CF₂H, OCH₂CH₂OCH₃, OCH₂CH₂N(CH₃)₂,3-trifluoromethylpyrid-6-ylmethoxy, 2-trifluoromethylpyrid-5-ylmethoxy,4-methylthiazol-5-ylmethoxy, 1-methylpyrazol-4-ylmethoxy,oxazol-5-ylmethylamino, CH₂OH, pyrid-3-ylmethylamino,benzimidazol-2-ylmethoxy, 4-trifluoromethylpyrid-6-ylmethoxy and3H-imidazo[4,5-b]pyridin-2-ylmethoxy.

p is preferably 0 or 1. p may be 0. p may be 1.

A subclass of the compounds of formula I are defined by formula IIA:

wherein R¹, V, W and Z have the same meanings as before.

In a particular embodiment of this subclass, R¹ is trifluoromethyl, V isH, Cl or F, and W is H, Cl, F or methyl, and at least one of V and W isH.

Within this subclass, preferred examples of groups represented by Zinclude H, Br, Cl, F, CN, NO₂, CF₃, OCF₃, CF₂H, SCF₃, amino,t-butylamino, dimethylamino, morpholin-4-yl, methyl, methoxymethyl,isopropyl, methoxy, methylthio, acetamido, N,N-dimethylcarbamoyl,methanesulphonyl, N,N-dimethylaminosulphonyl, 3-pyridoyl,(2-methyl-[1,2,4]triazol-3-yl)methoxy and(1-methyl-[1,2,4]triazol-3-yl)methoxy.

Z may have any of the values in the individual imidazopyrimidinesdisclosed herein. Likewise for R¹.

A second subclass of the compounds of formula I is defined by formulaIIB:

wherein R¹, V, W and Z have the same meanings as before.

In a particular embodiment of this subclass, R¹ is trifluoromethyl andone of V and W is H while the other is H, Cl or F.

Within this subclass, preferred examples of groups represented by Zinclude heteroarylmethoxy groups, such as(1,5-dimethylpyrazol-4-yl)methoxy, and (heteroarylmethyl)amino groups,such as (3-pyridylmethyl)amino, (1,5-dimethylpyrazol-4-ylmethyl)aminoand (1-methyl-5-trifluoromethylpyrazol-4-ylmethyl)amino.

Z may have any of the values in the individual imidazotriazinesdisclosed herein. Likewise for R¹.

A third subclass of the compounds of formula I is defined by formulaIIC:

wherein R¹, V, W and Z have the same meanings as before.

In a particular embodiment of this subclass, R¹ is selected from cyano,chloro, trifluoromethyl, formyl, —CO₂H, methoxycarbonyl, carbamoyl,—CH═NOH and 5-methylisoxazol-3-yl.

Within this subclass, V and W aptly both represent H, and Z aptlyrepresents trifluoromethyl.

Z may have any of the values in the individual imidazopyridinesdisclosed herein. Likewise for R¹.

Examples of specific compounds in accordance with the invention include:

-   3-(3-trifluoromethylphenyl)-7-trifluoromethylimidazo[1,2-a]pyrimidine;-   3-[3-cyanophenyl]-7-trifluoromethylimidazo[1,2-a]pyrimidine;-   7-{3-[(1,5-dimethyl-1H-pyrazol-4-yl)methoxy]-4-fluorophenyl}-3-trifluoromethylimidazo[1,2-b][1,2,4]triazine;-   3-(3-trifluoromethylphenyl)imidazo[1,2-a]pyridine-7-carboxamide;-   N-[2-fluoro-5-(3-trifluoromethylimidazo[1,2-b][1,2,4]triazin-7-yl)phenyl]-N-(3-pyridinylmethyl)amine;-   N-(1,5-dimethyl-1H-pyrazol-4-ylmethyl)-N-[2-fluoro-5-(3-trifluoromethylimidazo[1,2-b][1,2,4]triazin-7-yl)phenyl]amine;-   7-[4-fluoro-3-(1-methyl-5-trifluoromethyl-1H-pyrazol-4-ylmethoxy)phenyl]-3-trifluoromethylimidazo[1,2-b][1,2,4]triazine;-   3-[3-(1-methyl-1H-[1,2,4]triazol-3-ylmethoxy)phenyl]-7-trifluoromethylimidazo[1,2-a]pyrimidine;-   3-(2-fluoro-3-trifluoromethylphenyl)-7-trifluoromethylimidazo[1,2-a]pyrimidine;-   3-(3-trifluoromethoxyphenyl)-7-trifluoromethylimidazo[1,2-a]pyrimidine;-   and pharmaceutically acceptable salts thereof

Further examples include:

-   7-(4-fluoro-3-methoxyphenyl-3-trifluoromethylimidazo[1,2-b][1,2,4]triazine;-   methyl    3-(3-trifluoromethylphenyl)imidazo[1,2-a]pyridine-7-carboxylate;-   N-[2-fluoro-5-(3-trifluoromethylimidazo[1,2-b][1,2,4]triazin-7-yl)phenyl]-N-methyl-N-(3-pyridinylmethyl)amine;-   7-[4-fluoro-3-(pyridin-2-ylethoxy)phenyl]-3-(trifluoromethyl)imidazo[1,2-b][1,2,4]triazine;-   2-fluoro-5-[3-(trifluoromethyl)imidazo[1,2-b][1,2,4]triazin-7-yl]benzaldehyde;-   3-(3-trifluoromethylphenyl)imidazo[1,2-a]pyrimidine;-   7-[3(1H-benzimidazol-2-ylmethoxy)-4-fluorophenyl]-3-trifluoromethylimidazo[1,2-b][1,2,4]triazine;-   7-chloro-3-(3-trifluoromethylphenyl)imidazo[1,2-a]pyridine;-   3-(3-trifluoromethylphenyl)imidazo[1,2-a]pyridine-7-carboxaldehyde;-   3-(3-trifluoromethylphenyl)imidazo[1,2-a]pyridine-7-carboxaldehyde    oxime;-   3-(3-trifluoromethylphenyl)imidazo[1,2-a]pyridine-7-carbonitrile;-   7-(3-chlorophenyl)-3-trifluoromethylimidazo[1,2-b][1,2,4]triazine;-   3-trifluoromethyl-7-(3-trifluoromethylsulfanylphenyl)imidazo[1,2-b][1,2,4]triazine;-   7-[3-(1-methyl-1H-[1,2,4]triazol-3-ylmethoxy)phenyl]-3-trifluoromethylimidazo[1,2-b][1,2,4]triazine;-   and pharmaceutically acceptable salts thereof.

The compounds in accordance with the present invention have a goodbinding affinity (Ki) for the α5 subunit of the GABA_(A) receptor. In apreferred embodiment the compounds in accordance with the invention arebinding selective for the α5 subunit relative to the α1, α2 and α3subunits. In another preferred embodiment the compounds are functionallyselective for the α5 subunit as partial or full inverse agonists whilstsubstantially being antagonists at the α1, α2 and α3 subunits.

The invention provides pharmaceutical compositions comprising one ormore compounds of this invention and a pharmaceutically acceptablecarrier. Preferably these compositions are in unit dosage forms such astablets, pills, capsules, powders, granules, sterile parenteralsolutions or suspensions, metered aerosol or liquid sprays, drops,ampoules, transdermal patches, auto-injector devices or suppositories;for oral, parenteral, intranasal, sublingual or rectal administration,or for administration by inhalation or insufflation. For preparing solidcompositions such as tablets, the principal active ingredient is mixedwith a pharmaceutical carrier, e.g. conventional tableting ingredientssuch as corn starch, lactose, sucrose, sorbitol, talc, stearic acid,magnesium stearate, dicalcium phosphate or gums or surfactants such assorbitan monooleate, polyethylene glycol, and other pharmaceuticaldiluents, e.g. water, to form a solid preformulation compositioncontaining a homogeneous mixture of a compound of the present invention,or a pharmaceutically acceptable salt thereof. When referring to thesepreformulation compositions as homogeneous, it is meant that the activeingredient is dispersed evenly throughout the composition so that thecomposition may be readily subdivided into equally effective unit dosageforms such as tablets, pills and capsules. This solid preformulationcomposition is then subdivided into unit dosage forms of the typedescribed above containing from 0.1 to about 500 mg of the activeingredient of the present invention. Typical unit dosage forms containfrom 1 to 100 mg, for example 1, 2, 5, 10, 25, 50 or 100 mg, of theactive ingredient. The tablets or pills of the novel composition can becoated or otherwise compounded to provide a dosage form affording theadvantage of prolonged action. For example, the tablet or pill cancomprise an inner dosage and an outer dosage component, the latter beingin the form of an envelope over the former. The two components can beseparated by an enteric layer which serves to resist disintegration inthe stomach and permits the inner component to pass intact into theduodenum or to be delayed in release. A variety of materials can be usedfor such enteric layers or coatings, such materials including a numberof polymeric acids and mixtures of polymeric acids with such materialsas shellac, cetyl alcohol and cellulose acetate.

The liquid forms in which the novel compositions of the presentinvention may be incorporated for administration orally or by injectioninclude aqueous solutions, suitably flavoured syrups, aqueous or oilsuspensions, and flavoured emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles. Suitable dispersing or suspendingagents for aqueous suspensions include synthetic and natural gums suchas tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose,methylcellulose, polyvinyl-pyrrolidone or gelatin.

For the enhancement of cognition, a suitable dosage level is about 0.01to 250 mg/kg per day, preferably about 0.01 to 100 mg/kg of body weightper day, especially about 0.01 to 5 mg/kg of body weight per day, moreparticularly from 0.02 to 2.5 mg/kg of body weight per day. Thecompounds may be administered on a regimen of 1 to 4 times per day. Insome cases, however, dosage outside these limits may be used. A typicalbody weight is 70 kg.

The compounds in accordance with the present invention may be preparedby a process which comprises reacting a compound of formula III with acompound of formula IV:

wherein V, W, X, Y, Z and R¹ are as defined above, L¹ represents asuitable leaving group, and M¹ represents a boronic acid moiety —B(OH)₂or a cyclic ester thereof formed with an organic diol, e.g. pinacol orneopentyl glycol, or M¹ represents —Sn(Alk)₃ in which Alk represents aC₁₋₆ alkyl group, typically n-butyl; in the presence of a transitionmetal catalyst.

The leaving group L¹ is typically a halogen atom, e.g. bromo.

The transition metal catalyst of use in the reaction between compoundsIII and IV is suitably tetrakis(triphenylphosphine)-palladium( 0). Thereaction is conveniently carried out at an elevated temperature in asolvent such as N,N-dimethylacetamide, 1,2-dimethoxyethane,tetrahydrofuran or 1,4-dioxane, advantageously in the presence ofpotassium phosphate or sodium carbonate (when M¹ is —B(OH)₂ or esterthereof), or copper(l) iodide (when M¹ is Sn(Alk)₃). Alternatively, thetransition metal catalyst employed may be[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)(Pd(dppf)Cl₂), in which case the reaction may conveniently be carriedout at an elevated temperature in a solvent such asN,N-dimethylformamide, typically in the presence of potassium phosphate.

Where M¹ in the intermediates of formula IV above represents a boronicacid moiety —B(OH)₂ or a cyclic ester thereof formed with pinacol orneopentyl glycol, the relevant compound IV may be prepared by reactingbis(pinacolato)diboron or bis(neopentylglycolato)diborane with acompound of formula IVA:

wherein V, W and Z are as defined above, and L² represents a suitableleaving group; in the presence of a transition metal catalyst.

Typical leaving groups represented by L² includetrifluoromethanesulfonyloxy (triflyloxy); or a halogen atom such asbromo.

The transition metal catalyst of use in the reaction betweenbis(pinacolato)diboron or bis(neopentylglycolato)diborane and compoundIVA is suitably[1,1′-bis(diphenylphosphino)ferrocene]dichloro-palladium(II). Thereaction is conveniently carried out at an elevated temperature in asolvent such as 1,4-dioxane, optionally in admixture withdimethylsulfoxide, typically in the presence of Pd(dppf)Cl₂ and/orpotassium acetate.

Where L² in the intermediates of formula IVA above representstriflyloxy, the relevant compound IVA may be prepared by reacting thecorresponding compound of formula IV in which L² represents OH withN-phenyl-triflylimide, typically in the presence of triethylamine; orwith triflic anhydride, typically in the presence of pyridine

Where L¹ in the intermediates of formula III above represents bromo,this compound may be prepared by bromination of the correspondingcompound of formula V:

wherein X, Y and R¹ are as defined above; typically by treatment withbromine in acetic acid, in the presence of sodium acetate and optionallyalso potassium bromide.

The intermediates of formula V may be prepared by reactingchloroacetaldehyde or bromoacetaldehyde, or an acetal derivativethereof, e.g. the dimethyl or diethyl acetal thereof, with the requisitecompound of formula VI:

wherein X, Y and R¹ are as defined above.

Where chloroacetaldehyde or bromoacetaldehyde is utilised as one of thereactants, the reaction is conveniently carried out by heating thereactants under basic conditions in a suitable solvent, e.g. sodiummethoxide or sodium hydrogencarbonate in a lower alkanol such asmethanol and/or ethanol at the reflux temperature of the solvent. Wherean acetal derivative of chloroacetaldehyde or bromoacetaldehyde, e.g.the dimethyl or diethyl acetal thereof, is utilised as one of thereactants, the reaction is conveniently effected by heating thereactants under acidic conditions in a suitable solvent, e.g. aqueoushydrobromic acid in a lower alkanol such as methanol or ethanol,typically at the reflux temperature of the solvent.

In a still further procedure, the compounds according to the presentinvention may be prepared by a process which comprises reacting acompound of formula VI as defined above with a compound of formula VII:

wherein V, W and Z are as defined above, and L³ represents a suitableleaving group; under conditions analogous to those described above forthe reaction between bromoacetaldehyde and compound VI.

The leaving group L³ is suitably a halogen atom, e.g. bromo.

In a yet further procedure, the compounds according to the presentinvention wherein R¹ represents an aryl or heteroaryl moiety may beprepared by a process which comprises reacting a compound of formulaVIII with a compound of formula IX:

wherein V, W, X, Y, Z and M¹ are as defined above, R^(1a) represents anaryl or heteroaryl moiety, and L⁴ represents a suitable leaving group;in the presence of a transition metal catalyst.

The leaving group L⁴ is typically a halogen atom, e.g. chloro.

The transition metal catalyst of use in the reaction between compoundsVIII and IX is suitably tetrakis(triphenylphosphine)-palladium(0), inwhich case the reaction is conveniently effected at an elevatedtemperature in a solvent such as N,N-dimethylacetamide, typically in thepresence of potassium phosphate or in the presence of lithium chlorideand copper(I) iodide. Alternatively, the transition metal catalyst maysuitably be tris(dibenzylideneacetone)palladium(0), in which case thereaction is conveniently effected at an elevated temperature in asolvent such as 1,4-dioxane, typically in the presence oftri-tert-butylphosphine and cesium carbonate.

Where L⁴ in the compounds of formula IX above represents a halogen atom,these compounds correspond to compounds of formula I as defined abovewherein R¹ represents halogen, and they may therefore be prepared by anyof the methods described above for the preparation of the compoundsaccording to the invention.

In an alternative process a compound in accordance with the inventioncan be made by reacting a compound of formula V with a compound offormula X:

in which W, V and Z are as defined above, in the presence of palladiumacetate, triphenylphosphine and cesium carbonate in an anhydrous solventsuch as dry dioxan at about 90° C. for about 2 h.

Where they are not commercially available, the starting materials offormula IV, IVA, VI, VII, VIII and X may be prepared by methodsanalogous to those described in the accompanying Examples, or bystandard methods well known from the art.

It will be understood that any compound of formula I initially obtainedfrom any of the above processes may, where appropriate, subsequently beelaborated into a further compound of formula I by techniques known fromthe art. For example, a compound of formula I wherein R¹ representsC₁₋₆alkoxycarbonyl initially obtained may be hydrolysed to thecorresponding carboxylic acid, or reacted with ammonia to provide thecorresponding carboxamide, or reduced with lithium aluminium hydride tothe corresponding compound of formula I wherein R¹ representshydroxymethyl. The latter compound may then be oxidised to thecorresponding compound of formula I wherein R¹ represents formyl bytreatment with manganese dioxide. The formyl derivative thereby obtainedmay be condensed with a hydroxylamine derivative of formula H₂N—OR^(b)to provide a compound of formula I wherein R¹ represents —CH═NOR^(b).Furthermore, a compound of formula I wherein R¹ represents —CH═NOH maybe treated with triethylamine in the presence of1,1′-carbonyldiimidazole to afford a corresponding compound of formula Iwherein R¹ represents cyano. Alternatively, the compound of formula Iwherein R¹ represents formyl may be reacted with a Grignard reagent offormula R^(a)MgBr to afford a compound of formula I wherein R¹represents —CH(OH)R^(a), and this compound may in turn be oxidised usingmanganese dioxide to the corresponding compound of formula I wherein R¹represents —COR^(a). The latter compound may then be condensed with ahydroxylamine derivative of formula H₂N—OR^(b) to provide a compound offormula I wherein R¹ represents —CR^(a)═NOR^(b).

Similarly, compounds of formula I in which Z represents OCH₃ may beconverted to the corresponding phenols (1, Z=OH) by treatment with HBr,typically in acetic acid at reflux, or by treatment with borontribromide, typically in dichloromethane at −78° C. The phenols may bereacted with HO(CH₂)_(n)heteroaryl in the presence of adialkylazodicarboxylate (e.g.diisopropylazodicarboxylate) andtriphenylphosphine to provide the compounds of formula I in which Zrepresents —O(CH₂)_(n)heteroaryl, where n has the same meaning asbefore. The reaction is typically carried out at ambient temperature inTHF. Alternatively, the same products may be obtained by reaction of thephenols (I, Z=OH) with L⁵-(CH₂)_(n)heteroaryl in the presence of base,where L⁵ is a leaving group such as halogen, tosylate, mesylate ortriflate, and n has the same meaning as before.

Similarly, the compounds of formula I in which Z represents NO₂ may bereduced to the corresponding anilines (I, Z=NH₂) by standard methods(e.g. using tin(II)chloride), and the amino group converted to a varietyof derivatives by alkylation, acylation or diazotisation in usingstandard methods. In particular, the anilines may be reacted with thealdehydes heteroaryl(CH₂)_(n-1)CHO in the presence of sodiumtriacetoxyborohydride to provide the compounds of formula I wherein Zrepresents −NH(CH₂)_(n)heteroaryl, where n has the same meaning asbefore. This process may be repeated to provide compounds wherein Zrepresents —NR′(CH₂)_(n)heteroaryl wherein R is as defined above.

Where the above-described processes for the preparation of the compoundsaccording to the invention give rise to mixtures of stereoisomers, theseisomers may be separated by conventional techniques such as preparativechromatography. The novel compounds may be prepared in racemic form, orindividual enantiomers may be prepared either by enantiospecificsynthesis or by resolution. The novel compounds may, for example, beresolved into their component enantiomers by standard techniques such aspreparative HPLC, or the formation of diastereomeric pairs by saltformation with an optically active acid, such as(−)-di-p-toluoyl-d-tartaric acid and/or (+)-di-p-toluoyl-l-tartaricacid, followed by fractional crystallization and regeneration of thefree base. The novel compounds may also be resolved by formation ofdiastereomeric esters or amides, followed by chromatographic separationand removal of the chiral auxiliary.

During any of the above synthetic sequences it may be necessary and/ordesirable to protect sensitive or reactive groups on any of themolecules concerned. This may be achieved by means of conventionalprotecting groups, such as those described in Protective Groups inOrganic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W.Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, JohnWiley & Sons, 1991. The protecting groups may be removed at a convenientsubsequent stage using methods known from the art.

The following Examples illustrate the preparation of compounds accordingto the invention.

The compounds in accordance with this invention potently inhibit thebinding of [3H]-flumazenil to the benzodiazepine binding site of humanGABA_(A) receptors containing the α5 subunit stably expressed inLtk-cells.

Reagents

Phosphate buffered saline (PBS).

Assay buffer: 10 mM KH₂PO₄, 100 mM KCl, pH 7.4 at room temperature.

[3H]-Flumazenil (18 nM for α1β3γ2 cells; 18 nM for α2β3γ2 cells; 10 nMfor α3β3γ2 cells; 10 nM for α5β3γ2 cells) in assay buffer.

Flunitrazepam 100 μM in assay buffer.

Cells resuspended in assay buffer (1 tray to 10 ml).

Harvesting Cells

Supernatant is removed from cells. PBS (approximately 20 ml) is added.The cells are scraped and placed in a 50 ml centrifuge tube. Theprocedure is repeated with a further 10 ml of PBS to ensure that most ofthe cells are removed. The cells are pelleted by centrifuging for 20 minat 3000 rpm in a benchtop centrifuge, and then frozen if desired. Thepellets are resuspended in 10 ml of buffer per tray (25 cm×25 cm) ofcells.

Assay

Can be carried out in deep 96-well plates or in tubes. Each tubecontains:

-   -   300 μl of assay buffer.    -   50 μl of [3H]-flumazenil (final concentration for α1β3γ2: 1.8        nM; for α2β3γ2: 1.8 nM; for α3β3γ2: 1.0 nM; for α5β3γ2: 1.0 nM).    -   50 μl of buffer or solvent carrier (e.g. 10% DMSO) if compounds        are dissolved in 10% DMSO (total); test compound or        flunitrazepam (to determine non-specific binding), 10 μM final        concentration.    -   100 μl of cells.

Assays are incubated for 1 hour at 40° C., then filtered using either aTomtec or Brandel cell harvester onto GF/B filters followed by 3×3 mlwashes with ice cold assay buffer. Filters are dried and counted byliquid scintillation counting. Expected values for total binding are3000-4000 dpm for total counts and less than 200 dpm for non-specificbinding if using liquid scintillation counting, or 1500-2000 dpm fortotal counts and less than 200 dpm for non-specific binding if countingwith meltilex solid scintillant. Binding parameters are determined bynon-linear least squares regression analysis, from which the inhibitionconstant Ki can be calculated for each test compound.

The compounds of the accompanying Examples were tested in the aboveassay, and all were found to possess a Ki value for displacement of[3H]Ro 15-1788 from the α5 subunit of the human GABA_(A) receptor of 100nM or less, and some were at 1 nM or less.

The compounds of the present invention can be shown to enhance cognitionin the rat water maze test (Morris, Learning and Motivation, 1981, 12,239ff). This has been demonstrated for at least one compound describedherein. Further details of methodology for demonstrating that thepresent compounds enhance cognition can be found in WO-A-9625948.

EXAMPLE 13-(3-Trifluoromethylphenyl)-7-trifluoromethylimidazo[1,2-a]pyrimidineStep 1: 7-Trifluoromethylimidazo[1,2-a]pyrimidine

A mixture of 2-amino-4-trifluoromethylpyrimidine (prepared according toZanatta et al. in J. Heterocyclic Chem., 1997, 34(2), 509-513) (500 mg,3.1 mmol) and bromoacetaldehyde diethyl acetal (1.38 mL, 9.2 mmol) inethanol (10 mL) was treated with hydrobromic acid (0.5 mL of a 48%aqueous solution) and then heated at 70° C. for 12 h. The reaction wascooled to ambient temperature then pre-adsorbed onto silica.Purification by chromatography on silica eluting with dichloromethane(containing 1% conc. ammonia) on a gradient of methanol (1-5%) afforded7-trifluoromethylimidazo[1,2-a]pyrimidine (500 mg, 87%) as acream-coloured solid: δ (400 MHz, CDCl₃) 7.22 (1H, d, J 7), 7.74 (1H, d,J 1), 8.03 (1H, d, J 1), 8.67 (1H, d, J 7).

Step 2: 3-Bromo-7-trifluoromethylimidazo[1,2-a]pyrimidine

7-Trifluoromethylimidazo[1,2-a]pyrimidine (2.0 g, 10.7 mmol) and sodiumacetate (1.1 g, 13.4 mmol) were dissolved in methanol (30 mL) which hadbeen saturated with potassium bromide and this mixture was cooled to−10° C. before dropwise addition of bromine (1.86 g, 11.7 mmol) over 5min. On complete addition, the mixture was quenched by addition of 1Msodium sulfite solution (2 mL) and the solvent removed in vacuo. Theresidue was treated with water (100 mL) and saturated sodiumhydrogencarbonate solution (100 mL) and extracted with ethyl acetate(3×100 mL). The organics were combined then washed with brine (100 ml),dried over anhydrous sodium sulfate and evaporated to give an off-whitesolid. This solid was purified by silica gel chromatography eluting withdichloromethane and 1% conc. ammonia on a gradient of methanol (1-2%) togive 3-bromo-7-trifluoromethylimidazo[1,2-a]pyrimidine (1.98 g) as awhite solid: δ (400 MHz, CDCl₃) 7.35 (1H, d, J 7), 8.02 (1H, s), 8.62(1H, d, J 7).

Step 3:3-(3-Trifluoromethylphenyl)-7-trifluoromethylimidazo[1.2-a]pyrimidine

A mixture of 3-bromo-7-trifluoromethylimidazo[1,2-a]pyrimidine (300 mg,1.12 mmol), 3-trifluoromethylbenzeneboronic acid (429 mg, 2.24 mmol), 2NNa₂CO₃ solution (2.24 mL) and THF (4.5 mL) were degassed with a streamof N₂ for 5 min and then tetrakis(triphenylphosphine)palladium(0) (130mg, 10 mol %) was added and the reaction was heated at 70° C. for 90min. EtOAc (70 mL) was added and the mixture separated, washed withbrine (20 mL), dried (MgSO₄) and concentrated under reduced pressurewhile dry loading onto MgSO₄. The residue was purified by columnchromatography on silica using 40% Et₂O in iso-hexanes. The resultingmaterial was further purified by column chromatography on silica using35% EtOAc in iso-hexanes to give the desired imidazopyrimidine (83 mg,22%). ¹H NMR (400 MHz, d₆-DMSO) δ 7.54 (1H, d, J=7.1 Hz), 7.76-7.90 (2H,m), 8.04-8.15 (2H, m), 8.38 (1H, s), 9.30 (1H, d, J=7.1 Hz). m/z (ES⁺)332 (M+H⁺).

EXAMPLE 2 3-[3-Cyanophenyl]-7-trifluoromethylimidazo[1,2-a]pyrimidineStep 1: 3-(5,5-Dimethyl-1,3,2-dioxaborinan-2-yl)benzonitrile

A mixture of 3-iodobenzonitrile (2.0 g, 8.7 mmol),bis-(neopentylglycolato)diborane (2.17 g, 9.6 mmol), KOAc (2.6 g, 26.2mmol) and Pd(dppf)Cl₂ (356 mg, 5 mol %) in 1,4-dioxane (60 mL) wasdegassed with a stream of N₂ for 10 min and then heated at 110° C. for16 h. The reaction mixture was concentrated under reduced pressure anddiethyl ether (150 mL) was added. This mixture was extracted with 4NNaOH (3×50 mL) and the combined basic extracts were neutralised withconc. HCl and then extracted with DCM (3×100 mL). The combined organicfiltrates were washed with brine (50 mL) and dried (MgSO₄) to yield thedesired boronate ester (1.82 mg, 97%). ¹H NMR (360 MHz, CDCl₃) δ 1.03(6H, s), 3.78 (4H, s), 7.44 (1H, t, J=7.6 Hz), 7.67 (1H, t, J=7.6 Hz),7.99 (1H, d, J=7.6 Hz), 8.08 (1H, s).

Step 2: 3-[3-Cyanophenyl]-7-trifluoromethylimidazo[1,2-a]pyrimidine

The reaction was carried out as described in step 3 of Example 1 using3-bromo-7-trifluoromethylimidazo[1,2-a]pyrimidine (300 mg, 1.1 mmol),the boronate ester (487 mg, 2.2 mmol), 2N Na₂CO₃ solution (2.2 mL) andTHF (4.5 mL) tetrakis(triphenylphosphine) palladium(0) (130 mg, 10 mol%) at 70° C. for 90 min. After work up the residue was purified twice bycolumn chromatography on silica using 40% Et₂O in toluene and then 55%EtOAc in iso-hexanes to give the desired imidazopyrimidine (40 mg, 12%).¹H NMR (400 MHz, d₆-DMSO) δ 7.55 (1H, d, J=7.0 Hz), 7.79 (1H, t, J=7.8Hz), 7.95 (1H, d, J=7.8 Hz), 8.10 (1H, d, J=7.8 Hz), 8.29 (1H, s), 8.38(1H, s), 9.41 (1H, d, J=7.0 Hz). m/z (ES⁺) 289 (M+H⁺).

EXAMPLE 37-(4-Fluoro-3-methoxyphenyl-3-trifluoromethylimidazo[1,2-b][1,2,4]triazineStep 1: 3-Amino-5-trifluoromethyl-1,2,4-triazine

To a stirred solution of sodium acetate trihydrate (22.62 g, 166.2 mmol)in water (80 mL) was added 1,1-dibromo-3,3,3-trifluoroacetone (21.57 g,79.9 mmol). The solution was heated at reflux under nitrogen for 30 min,then allowed to cool to room temperature before adding solidaminoguanidine bicarbonate (10.88 g, 79.9 mmol). The resulting paleyellow solution (pH 5) was stirred at room temperature for 3 h, then 4 Naqueous NaOH solution (40 mL, 160 mmol) was added causing a precipitateto appear. The mixture (pH 10) was stirred under nitrogen for a further39 h. The solid was collected by filtration, washed with water and driedat 60° C. under vacuum to give 6.96 g of a mixture of two isomers in a28:72 ratio. This was further purified by flash chromatography (silicagel, 30% EtOAc/isohexane), then recrystallised from ethanol to afford3.53 g (27%) of the title compound: ¹H NMR (400 MHz, DMSO-d₆) δ 8.00(2H, br s), 9.08 (1H, s).

Step 2: 3-Trifluoromethylimidazo[1,2-b][1,2,4]triazine

A stirred mixture of bromoacetaldehyde diethyl acetal (2.30 mL, 14.8mmol) in concentrated hydrobromic acid (0.73 mL) and water (0.73 mL) washeated at reflux for 2 h, then poured into ethanol (25 mL). The solutionwas neutralised to pH 7 with solid sodium hydrogencarbonate, thenfiltered. To the filtrate was added3-amino-5-trifluoromethyl-1,2,4-triazine (1.08 g, 6.14 mmol) and themixture was stirred at 60° C. for 20 h, then 80° C. for 23 h. Themixture was evaporated in vacuo, and the residue was purified by flashchromatography (silica gel, 35-50% EtOAc/isohexane) to give 0.259 g(22%) of the title compound: ¹H NMR (360 MHz, CDCl₃) δ 8.20 (1H, d, J0.8 Hz), 8.30 (1H, d, J 0.9 Hz), 8.73 (1H, s).

Step 3:7-(4-Fluoro-3-methoxyphenyl)-3-trifluoromethylimidazo[1,2-b][1,2,4]triazine

A mixture of 3-trifluoromethylimidazo[1,2-b][1,2,4]triazine (3.2 g, 17mmol), palladium acetate (185 mg, 5 mol %), triphenylphosphine (672 mg,15 mol %), cesium carbonate (8.2 g, 25 mmol) and4-bromo-1-fluoro-2-methoxybenzene (4.1 g, 20 mmol) in dry 1,4-dioxan(100 mL) under an inert atmosphere was heated at 90° C. for 20 h. Thecooled reaction mixture was diluted with ethyl acetate, filtered throughHyflo and solvents removed in vacuo. The residue was redissolved inethyl acetate, washed with water and saturated brine then dried MgSO₄),filtered and concentrated in vacuo. Crystallisation from ethyl acetate,washing with ethanol and drying gave7-(4-fluoro-3-methoxyphenyl)-3-trifluoromethylimidazo[1,2-b][1,2,4]triazineas a coloured solid (3.5 g). ¹H NMR (400 MHz, CDCl₃) δ 4.01 (3H, s),7.26 (1H, dd, J 11.0 and 8.6), 7.61-7.64 (1H, m), 7.76 (1H, dd, J 2.2and 8.0), 8.57 (1H, s), 8.81 (1H, s).

EXAMPLE 47-{[3-(1,5-Dimethyl-1H-pyrazol-4-yl)methoxy]-4-fluorophenyl}-3-trifluoromethylimidazo[1,2-b]1,2,4]triazine

Step 1: Intermediate 1: (1,5-Dimethyl-1H-pyrazol-4-yl)-methanol

Sodium borohydride (0.75 g, 19.3 mmol) was added in portions over 15 minto a stirred solution of 1,5-dimethyl-1H-pyrazole-4-carbaldehyde (2.40g, 19.3 mmol; Zh. Org. Khim. (1973), 9(4), 815-817) in dry methanol (30mL) at 0° C. under an inert atmosphere. After 1 h the solution wasallowed to warm to ambient temperature then partitioned between diethylether and water. Aqueous washings were concentrated in vacuo andextracted with dichloromethane. These extracts were washed with aminimum of saturated brine then dried (MgSO₄), filtered and evaporatedin uacuo to give (1,5-dimethyl-1H-pyrazol-4-yl)-methanol as a solid (1.2g). ¹H NMR (360 MHz, CDCl₃) δ 1.30 (1H, s), 2.28 (3H, s), 3.78 (3H, s),4.51 (2H, s), 7.41 (1H, s). m/z (ES⁺) 127 (M+H⁺).

Step 2:2-Fluoro-5-(3-trifluoromethylimidazo[1.2-b][1,2,4]triazin-7-yl)-phenol

Boron tribromide (4.5 mL, 47 mmol) was added dropwise to a stirredsolution of7-(4-fluoro-3-methoxyphenyl)-3-trifluoromethylimidazo[1,2-b][1,2,4]triazine(2.5 g, 8 mmol) in dry dichloromethane (100 mL) at −78° C. The coolingbath was removed after 30 min and the mixture allowed to warm to ambienttemperature. Reaction was quenched using methanol at 0° C. then pouredinto a saturated aqueous solution of sodium hydrogen carbonate. Theprecipitate was filtered off, washed with water and dried in vacuo at80° C. to give2-fluoro-5-(3-trifluoromethylimidazo[1,2-b][1,2,4]triazin-7-yl)-phenol(Intermediate 1) as an orange solid (1.8 g). ¹H NMR (400 MHz, d6-DMSO) δ7.38 (1H, dd, J 8.6 and 11.0), 7.60-7.63 (1H, m), 7.88 (1H, dd, J 2.2and 8.4), 8.83 (1H, s), 9.32 (1H, s), 10.27 (1H, s). m/z (ES⁺) 299(M+H⁺).

Step 3:7-{[3-(1,5-Dimethyl-1H-pyrazol-4-yl)methoxy]-4-fluorophenyl}-3-trifluoromethylimidazo[1,2-b][1,2,4]triazine

Diisopropylazodicarboxylate (0.85 mL, 3.99 mmol) was added dropwise over10 min to a stirred solution of2-fluoro-5-(3-trifluoromethylimidazo[1,2-b][1,2,4]triazin-7-yl)-phenol(1.0 g, 3.35 mmol), triphenylphosphine (1.05 g, 3.97 mmol) and(1,5-dimethyl-1H-pyrazol-4-yl)-methanol (0.50 g, 3.97 mmol) in drytetrahydrofuran (50 mL). After stirring at ambient temperature overnightthe mixture was adsorbed onto silica and solvent removed in vacuo.Purification by column chromatography on a gradient of ethylacetate-isohexane (20-100%) and trituration with 50% diethylether-isohexane gave7-{[3-(1,5-dimethyl-1H-pyrazol-4-yl)methoxy]-4-fluorophenyl}-3-trifluoromethylimidazo[1,2-b][1,2,4]triazineas an orange solid (0.68 g). ¹H NMR (400 MHz, d6-DMSO) δ 2.28 (3H, s),3.73 (3H, s), 5.11 (2H, s), 7.45 (1H, dd, J 8.6 and 11.3), 7.48 (1H, s),7.85-7.88 (1H, m), 8.11 (1H, dd, J 2.2 and 8.0), 8.97 (1H, s), 9.36 (1H,s). m/z (ES⁺) 407 (M+H⁺).

EXAMPLE 5 Methyl3-(3-trifluoromethylphenyl)imidazo[1,2-a]pyridine-7-carboxylate

A mixture of methyl 3-bromoimidazo[1,2-a]pyridine-7-carboxylate(WO0138326) (250 mg, 0.98 mmol), 3-trifluoromethylbenzeneboronic acid(280 mg, 1.47 mmol), 2M Na₂CO₃ solution (1.5 mL) and THF (5 mL) wasdegassed with a stream of N₂ for 5 min.Tetrakis(triphenylphosphine)palladium(0) (57 mg, 10 mol %) was added andthe reaction was heated at reflux for 3 h. The mixture was thenpartitioned between CH₂Cl₂ (20 mL) and water (20 mL) and the organicswere washed with brine (20 mL), dried (MgSO₄) and concentrated underreduced pressure. The residue was purified by column chromatography onsilica using 80% EtOAc in iso-hexanes to afford the desiredimidazopyridine (195 mg, 62%). ¹H NMR (360 MHz, d₆-DMSO) δ 3.31 (3H, s),7.24 (1H, dd, J 2.0, 7.2 Hz), 7.80-7.87 (2H, m), 8.05-8.08 (2H, m), 8.13(1H, s), 8.19-8.21 (1H, m) 8.75 (1H, d, J 7.2 Hz). m/z (ES⁺) 321 (MH⁺).

EXAMPLE 63-(3-Trifluoromethylphenyl)imidazo[1,2-a]pyridine-7-carboxamide

A mixture of methyl(3-trifluoromethylphenyl)imidazo[1,2-a]pyridine-7-carboxylate (100 mg,0.31 mmol) and a 2 M solution of ammonia in MeOH (15 mL) was heated in asealed tube at 100° C. for 8 h. On cooling, 5 mL of a 25% aqueousammonia solution was added and the mixture sealed and heated at 100° C.for a further 18 h, then cooled and concentrated under reduced pressure.The residue was purified by column chromatography on silica using 5%MeOH in CH₂Cl₂ to afford the desired imidazopyridine (32 mg, 34%). ¹HNMR (400 MHz, d₆-DMSO) δ 7.44 (1H, dd, J 2.0 and 7.0), 7.58-7.60 (1H,m), 7.80-7.82 (2H, m), 8.03-8.05 (3H, m), 8.20-8.22 (1H, m), 8.27-8.28(1H, m), 8.63 (1H, dd, J 0.8 and 7.0). m/z (ES⁺), 306 (MH⁺).

EXAMPLE 7N-[2-Fluoro-5-(3-trifluoromethylimidazo[1,2-b][1,2,4]triazin-7-yl)phenyl]-N-(3-pyridinylmethyl)amineStep 1:2-Fluoro-5-(3-trifluoromethylimidazo[1,2-b][1,2,4]triazin-7-yl)phenylamine

A mixture of 4-bromo-1-fluoro-2-nitrobenzene (10 g, 0.045 mol),potassium acetate (13.3 g, 0.135 mol) and bis(neopentylglycolato)diboron(10.6 g, 0.047 mol) in 1,4-dioxane (100 mL) was degassed with N₂.[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium (II), complexwith DCM (1:1) (0.92 g, 1.1 mmol) was added and the mixture heated atreflux for 24 h. The mixture was evaporated in vacuo and the residuepartitioned between DCM and water then filtered to remove an undissolvedblack solid. The DCM layer was retained, dried (MgSO₄), filtered andevaporated to dryness to give2-(4-fluoro-3-nitrophenyl)-5,5-dimethyl-[1,3,2]dioxaborinane as a brownoil (17 g) which was used without purification in the next step. ¹H NMR(360 MHz, CDCl₃) δ 1.03 (6H, s), 3.78 (4H, s), 7.21-7.26 (1H, m),7.99-8.05 (1H, m), 7.44-8.47 (1H, m).

A mixture of 7-bromo-3-trifluoromethylimidazo[1,2-b][1,2,4]triazine (10g, 0.037 mol), the foregoing boronate ester (13.5 g, 0.061 mol) and 2NNa₂CO₃ (61 mL, 0.12 mol) in THF (300 mL) was degassed with N₂.Tetrakis(triphenylphosphine)palladium(0) (2.14 g, 1.85 mmol) was addedand the mixture heated at reflux for 24 h. The mixture was evaporated inuacuo and the residue partitioned between DCM and water. The aqueouslayer was re-extracted with DCM and the combined organics washed twicewith 4N NaOH, then twice with brine and dried (MgSO₄). The solvent wasevaporated in vacuo to give the crude residue which was purified onsilica eluting with DCM.7-(4-Fluoro-3-nitrophenyl)-3-trifluoromethylimidazo[1,2-b][1,2,4]triazinewas isolated as an orange solid (7.2 g) after trituration with ether,filtration and drying. A second crop (0.8 g, combined yield 65%) wasisolated by trituration of the evaporated liquors. MS (ES⁺) 328 (M+1).

A mixture of the foregoing nitro compound (1.25 g, 3.8 mmol),tin(II)chloride (3.0 g, 15.8 mmol) in EtOH (100 mL) was stirred at 25°C. for 60 h. Aqueous NH₃ (33%) (50 mL) was added, stirred for 5 min,then evaporated to dryness. The residue was triturated with diethylether and filtered. This procedure was repeated 3 times, MgSO₄ added,and the mixture evaporated to dryness and loaded onto a silica column.The column was eluted with 10% EtOAc/isohexane then 20% EtOAc/isohexane.The title compound was isolated as a yellow solid (300 mg, 27%). ¹H NMR(400 MHz, d₆-DMSO) δ 5.42 (2H, s), 7.20 (2H, dd, J 8.5 & 11.4 Hz), 7.31(1H, ddd, J=2.2, 4.4 & 8.4 Hz), 7.58 (1H, dd, J 2.2 & 8.7 Hz), 8.73 (1H,s), 9.28 (1H, s). MS (ES⁺) 298 (M+1).

Step 2:N-[2-Fluoro-5-(3-trifluoromethylimidazo[1,2-b][1,2,4]triazin-7-yl)phenyl]-N-(3-pyridinylmethyl)amine

A solution of the foregoing aniline (150 mg, 0.51 mmol) and3-pyridinecarboxaldehyde (54 mg, 0.51 mmol) in AcOH (10 mL) was stirredat 25° C. for 7 h. Sodium triacetoxyborohydride (130 mg, 0.61 mmol) wasadded and the reaction stirred for 18 h. The mixture was evaporated todryness, the residue partitioned between DCM and water and thenneutralised with saturated aqueous NaHCO₃. The DCM layer was separatedand the aqueous phase re-extracted with DCM. The combined organics weredried (MgSO₄), and concentrated to give the crude residue which waspurified by silica chromatography eluting 10% diethyl ether/DCM then 1%MeOH/DCM to give an orange solid (102 mg, 52%). ¹H NMR (400 MHz,d₆-DMSO) δ 4.47 (2H, d, J 6.2 Hz), 6.62-6.70 (1H, m), 7.24 (1H, dd,J=8.2 & 11.7 Hz), 7.34-7.43 (2H, m), 7.51 (1H, dd, J 2.0 & 8.6 Hz), 7.85(1H, d, J 7.8 Hz), 8.45 (1H, br s), 8.70 (1H, br s), 8.79 (1H, s), 9.21(1H, s). MS (ES⁺) 389 (M+1).

EXAMPLE 8N-(1,5-Dimethyl-1H-pyrazol-4-ylmethyl)-N-[²-fluoro-5-(3-trifluoromethylimidazo[1,2-b][1,2,4]triazin-7-yl)phenyl]amine

The title compound was obtained as a red solid (50 mg, 46%) using theprocedure described in Example 7, Step 2 using1,5-dimethyl-1H-pyrazole-4-carbaldehyde instead of3-pyridinecarboxaldehyde. ¹H NMR (400 MHz, d₆-DMSO) δ 2.27 (3H, s), 3.66(3H, s), 4.18 (2H, d, J 5.7 Hz), 5.92-5.97 (1H, m), 7.22 (1H, dd, J 8.4& 11.7 Hz), 7.39 (1H, s), 7.42 (1H, dd, J 2.1, 4.4 & 8.3 Hz), 7.58 (1H,dd, 2.1 & 8.5 Hz), 8.85 (1H, s), 9.29 (1H, s). MS (ES⁺) 406 (M+1).

EXAMPLE 97-[4-Fluoro-3-(1-methyl-3-trifluoromethyl-1H-pyrazol-4-ylmethoxy)phenyl]-3-trifluoromethylimidazo[1,2-b][1,2,4]triazine

A solution of 1-methyl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acidethyl ester (2.52 g, 11.3 mmol) in THF (40 mL) was added to a stirredsolution of 1.0 M LiAlH₄ in diethyl ether (45 mL, 45 mmol). Uponcomplete addition the reaction was heated at 50° C. for 5 h. The cooledreaction mixture was quenched cautiously by addition of water (10 mL).2N HCl (100 mL) and DCM (100 mL) were added and the mixture stirred for30 min. The organic phase was separated and the aqueous re-extractedwith DCM. The combined organics were washed with brine, dried (MgSO₄)and concentrated in uacuo. The crude residue was purified on silica,eluting 5% MeOH/DCM, to give(1-methyl-5-trifluoromethyl-1H-pyrazol-4-yl)methanol as a pale yellowoil (1.46 g, 72%). ¹H NMR (360 MHz, CDCl₃) δ 3.93 (3H, s), 4.66 (2H, s),7.46 (1H, s).

The foregoing alcohol was reacted with2-fluoro-5-(3-trifluoromethylimidazo[1,2-b][1,2,4]triazin-7-yl)phenol bythe procedure described in Example 4, Step 3 using diethylazodicarboxylate instead of diisopropyl azodicarboxylate. The titlecompound was isolated as a orange solid (65 mg, 70%). ¹H NMR (400 MHz,d₆-DMSO) δ 3.93 (3H, s), 5.22 (2H, s), 7.46 (1H, dd, J 8.6, & 11.2 Hz),7.90 (1H, ddd, J 2.0, 4.2 & 8.4 Hz), 8.07 (1H, dd, J 2 & 8 Hz), 8.14(1H, s), 8.97 (1H, s), 9.36 (1H, s). MS (ES⁺) 461 ( M+1).

EXAMPLE 103-[3-(1-Methyl-1H-[1,2,4]triazol-3-ylmethoxy)phenyl]-7-trifluoromethylimidazo[1,2-a]pyrimidineStep 1: 3-(3-Bromophenoxymethyl)-1-methyl-1H-[1,2,4]triazole

A mixture of 3-bromophenol (2.0 g, 11.6 mmol),3-chloromethyl-1-methyl-1H-[1,2,4]triazole hydrochloride (WO 9850385)(1.94 g, 11.6 mmol) and K₂CO₃ (4.79 g, 34.7 mmol) in DMF (20 mL) wasstirred overnight at 25° C. under N₂. Water (200 mL) was added and theorganics were extracted with EtOAc (2×100 mL). The combined organicextracts were washed with water (2×100 mL), brine (50 mL) then dried(MgSO₄) and concentrated under reduced pressure. The crude residue waspurified by column chromatography on silica using 100% EtOAc to yieldthe ether (1.31 g, 42%). ¹H NMR (360 MHz, CDCl₃) δ 8.04 (1H, s), 7.20(1H, s), 7.18-7.06 (2H, m), 6.97 (1H, d, J=7.9 Hz), 5.12 (2H, s), 3.93(3H, s).

Step 2:3-[3-(5,5-Dimethyl-[1.3.2]dioxaborinan-2-yl)phenoxymethyl]-1-methyl-1H-[1,2,4]triazole

The reaction was carried out according to Example 2, Step 1 using3-(3-bromophenoxymethyl)-1-methyl-1H-[1,2,4]triazole (1.31 g, 4.9 mmol),bis-(neopentylglycolato)diborane (1.16 g, 5.2 mmol), KOAc (1.44 g, 14.7mmol) and Pd(dppf)Cl₂ (200 mg, 5 mol %) in 1,4-dioxane (70 mL) to yieldthe desired boronate ester (1.22 g, 83%). ¹H NMR (360 MHz, CDCl₃) δ 8.04(1H, s), 7.47 (1H, s), 7.41 (1H, d, J=7.2 Hz), 7.27 (1H, t, J=7.3 Hz),7.11 (1H, d, J=7.3 Hz), 5.16 (2H, s), 3.93 (3H, s), 3.77 (4H, s), 1.03(6H,s). m/z (ES⁺) 302 (M+H⁺).

Step 3:3-[3-(1-Methyl-1H-[1,2,4]triazol-3-ylmethoxy)phenyl]-7-trifluoromethylimidazo[1,2-a]pyrimidine

The reaction was carried out as described in Example 1 using3-bromo-7-trifluoromethylimidazo[1,2-a]pyrimidine (300 mg, 1.1 mmol),the foregoing boronate ester (679 mg, 2.2 mmol), andtetrakis(triphenylphosphine) palladium(0) (130 mg, 10 mol %) in 2MNa₂CO₃ solution (2.2 mL) and THF (4.5 mL) at 65° C. for 3 h. After workup, the residue was purified by column chromatography on silica using70-100% EtOAc/iso-hexane containing 1% MeOH and 1% Et₃N to give thedesired imidazopyrimidine (252 mg, 60%). ¹H NMR (360 MHz, d₆-DMSO) δ9.38 (1H, d, J=7.2 Hz), 8.50 (1H, s), 8.28 (1H, s), 7.58-7.45 (2H, m),7.32 (1H, d, J=7.8 Hz), 7.15 (1H, dd, J=7.9, 2.1 Hz), 5.18 (2H, s), 3.88(3H, s). m/z (ES⁺) 375 (M+H⁺).

EXAMPLE 113-(2-Fluoro-3-trifluoromethylphenyl)-7-trifluoromethylimidazo[1.2-a]pyrimidineStep 1:2-(2-Fluoro-3-trifluoromethylphenyl)-5,5-dimethyl-[1,3,2]dioxaborinaneand 2-fluoro-3-trifluoromethylphenylboronic acid

The reaction was carried out according to Example 2, Step 1 using1-bromo-2-fluoro-3-trifluoromethylbenzene (1.5 g, 6.2 mmol),bis(neopentylglycolato)diborane (1.46 g, 6.5 mmol), KOAc (1.21 g, 12.3mmol) and Pd(dppf)Cl₂ (252 mg, 5 mol %) in 1,4-dioxane (50 mL) to yielda mixture of the boronic acid and the boronate ester (1:2, 498 mg, ca.32%). Boronic acid: ¹H NMR (400 MHz, CDCl₃) δ 8.07-8.02 (1H, m),7.75-7.69 (1H, m), 7.33-7.28 (1H, m). Boronate ester: ¹H NMR (400 MHz,CDCl₃) δ7.93-7.86 (1H, m), 7.67-7.61 (1H, m), 7.22-7.17 (1H, m). 3.80(4H, s), 1.05 (6H,s).

Step 2:3-(2-Fluoro-3-trifluoromethylphenyl)-7-trifluoromethylimidazo[1,2-a]pyrimidine

The reaction was carried out as described in Example 1 using3-bromo-7-trifluoromethylimidazo[1,2-a]pyrimidine (240 mg, 0.9 mmol),the mixture of the boronate and boronic acid (498 mg, ca. 1.98 mmol),and tetrakis(triphenylphosphine)palladium(0) (104 mg, 10 mol %) in 2MNa₂CO₃ solution (1.8 mL) and THF (3.6 mL) at 65° C. for 3 h. After workup, the residue was purified by column chromatography on silica using35% EtOAc/iso-hexane to give the desired imidazopyrimidine (232 mg,74%). ¹H NMR (400 MHz, d₆-DMSO) δ 9.15 (1H, d, J=7.0 Hz), 8.33 (1H, s),8.09 (1H, t, J=6.6 Hz), 7.97 (1H,t, J=6.3 Hz), 7.68-7.58 (2H, m). m/z(ES⁺) 350 (M+H⁺).

EXAMPLE 123-(3-Trifluoromethoxyphenyl)-7-trifluoromethylimidazo[1,2-a]pyrimidine

The reaction was carried out as described in Example 1 using3-bromo-7-trifluoromethylimidazo[1,2-a]pyrimidine (300 mg, 1.1 mmol),3-(trifluoromethoxy)benzeneboronic acid (465 mg, 2.2 mmol), andtetrakis(triphenylphosphine)palladium(0) (130 mg, 10 mol %) in 2M Na₂CO₃solution (2.3 mL) and THF (4.5 mL) at 70° C. for 90 min. After work up,the residue was purified twice by column chromatography on silica using30% EtOAc/iso-hexane and then 30% Et₂O/toluene to give the desiredimidazopyrimidine (160 mg, 42%). ¹H NMR (360 MHz, d₆-DMSO) δ 9.30 (1H,d, J=7.2 Hz), 8.35 (1H, s), 7.84-7.80 (1H, m), 7.81 (1H, s), 7.73 (1H,t, J=8.0 Hz), 7.55 (1H, d, J=7.2 Hz), 7.51 (1H, d, J=8.0 Hz). m/z (ES⁺)348 (M+H⁺).

EXAMPLE 13N-[2-Fluoro-5-(3-trifluoromethylimidazo[1,2-b][1,2,4]triazin-7-yl)phenyl]-N-methyl-N-(3-pyridinylmethyl)amine

The title compound was obtained as an orange solid (18 mg, 94%) usingthe procedure described in Example 5, Step 2 usingN-[2-fluoro-5-(3-trifluoromethylimidazo[1,2-b][1,2,4]triazin-7-yl)phenyl]-N-(3-pyridinylmethyl)amineas the amine and paraformaldehyde instead of 3-pyridinecarboxaldehyde.¹H NMR (400 MHz, d₆₋DMSO) δ 2.85 (3H, s), 4.41 (2H, s), 7.34-7.43 (2H,m), 7.70-7.80 (3H, m), 8.46 (1H, dd, J=4.7 and 1.6 Hz), 8.53 (1H, d,J=1.6 Hz), 8.88 (1H, s), 9.30 (1H, s). MS (ES⁺) 403 (M+1).

EXAMPLE 147-[4-Fluoro-3-(pyridin-2-ylethoxy)phenyl]-3-(trifluoromethylimidazo[1,2-b][1,2,4]triazine

A mixture of2-fluoro-5-(3-trifluoromethylimidazo[1,2-b][1,2,4]triazin-7-yl)-phenol(60 mg, 0.2 mmol), polymer-supported PPh₃ (133 mg at 3 mmol/g, 0.4 mmol)and 2-(2-hydroxyethyl)pyridine (49 mg, 0.4 mmol) in THF (3 mL) wastreated with diethyl azodicarboxylate (69 mg, 0.4 mmol) and stirred at25° C. for 2 h. The reaction mixture was filtered to remove the polymersupported PPh₃ and the filtrate evaporated to give the crude residue.The residue was dissolved in DMSO at 20 mg/mL and a portion (2 mL) ofthe crude solution was purified by mass-triggered preparative HPLC. Thetitle compound was isolated (18 mg). ¹H NMR (400 MHz, d₆₋DMSO) δ 3.28(2H, t, J=6.6 Hz), 4.56 (2H, t, J=6.6 Hz), 7.23-7.29 (1H, m), 7.38-7.47(2H, m), 7.53 (1H, dt, J=7.8 and 1.9 Hz), 7.84 (1H, ddd, J=8.4, 4.3 and2.4 Hz), 7.98 (1H, dd, J=8.4 and 2.4 Hz), 8.51-8.54 (1H, d, J=5.9 Hz),8.95 (1H, s), 9.35 (1H, s). MS (ES⁺) 404 (M+1).

EXAMPLE 152-Fluoro-5-[3-(trifluoromethyl)imidazo[1,2-b][1,2,4]triazin-7-yl]benzaldehyde

The title compound was isolated as a yellow solid (880 mg, 54%) usingthe procedure in Example 3, Step 3 using 5-bromo-2-fluorobenzaldehydeinstead of 4-bromo-1-fluoro-2-methoxybenzene. ¹H NMR (360 MHz, d₆₋DMSO)δ 7.69 (1H, dd, J=10.2 and 8.6 Hz), 8.54 (1H, ddd, J=8.6, 4.9 and 2.4Hz), 8.71 (1H, dd, J=6.6 and 2.4 Hz), 8.99 (1H, s), 9.42 (1H, s), 10.3(1H, s). MS (ES⁺) 311 (M+1).

EXAMPLE 16 3-(3-Trifluoromethylphenyl)imidazo[1,2-a]pyrimidine

3-(3-Trifluoromethylphenyl)imidazo[1,2-a]pyrimidine was obtained as acolourless solid (100 mg, 38%) using the procedure described in Example1, Step 3 using 3-bromoimidazo[1,2-a]pyrimidine (WO 01/90108) (0.2 g,1.0 mmol) and 3-(trifluoromethyl)benzene boronic acid (0.25 g, 1.3mmol). ¹H NMR (400 MHz, CDCl₃) δ 6.96 (1H, m), 7.66-7.76 (3H, m), 7.81(1H, s), 7.97 (1H, s), 8.60-8.64 (2H, m). m/z (ES⁺) 264 (M+H⁺).

EXAMPLE 177-[3-(1H-Benzimidazol-2-ylmethoxy)-4-fluorophenyl]-3-trifluoromethylimidazo[1,2-b][1,2,4]triazine

2-Fluoro-5-(3-trifluoromethylimidazo[1,2-b][1,2,4]triazin-7-yl)-phenol(75 mg, 0.25 mmol) and 2-(chloromethyl)benzimidazole hydrochloride (52mg, 30 mmol) were coupled using the procedure described in Example 10,Step 1 to give the title compound as a yellow solid (23 mg, 21%). ¹H NMR(400 MHz, CDCl₃) δ 5.57 (2H, s), 7.28-7.35 (3H, m), 7.52-7.80 (3H, m),7.95 (1H, dd J=8.0 and 2.2 Hz), 8.47 (1H, s), 8.52 (1H, s). m/z (ES⁺)429 (M+H⁺).

EXAMPLE 18 7-Chloro-3-(3-trifluoromethylphenyl)imidazo[1,2-a]pyridine

A mixture of 3-bromo-7-chloroimidazo[1,2-a]pyridine (WO 01/38326),3-trifluoromethylbenzeneboronic acid, 2 M Na₂CO₃ solution, andtetrakis(triphenylphosphine)palladium(0) in THF were reacted asdescribed in Example 5 to afford the desired imidazopyridine (312 mg,62%). ¹H NMR (400 MHz, d₆₋DMSO) δ 7.42 (1H, dd, J=7.4 and 2.3 Hz), 7.87(1H, t, J=7.8 Hz), 7.95 (1H, d, J=7.8 Hz), 8.04 (1H, d, J=7.4 Hz), 8.08(1H, s), 8.19 (1H, dd, J=2.3 and 0.8 Hz), 8.39 (1H, s) 8.77 (1H, dd,J=7.4 and 0.8 Hz). m/z (ES⁺) 297 (MH⁺).

EXAMPLE 193-(3-Trifluoromethylphenyl)imidazo[1,2-a]pyridine-7-carboxaldehyde

A mixture of 3-bromoimidazo[1,2-a]pyridine-7-carboxaldehyde (WO01/38326), 3-trifluoromethylbenzeneboronic acid, 2 M Na₂CO₃ solution andtetrakis(triphenylphosphine)palladium(0) in THF were reacted asdescribed in Example 5 to afford the desired imidazopyridine (150 mg,69%). ¹H NMR (400 MHz, d₆₋DMSO) δ 7.34 (1H, dd, JJ=7.0 and 1.6 Hz),7.81-7.87 (2H, m), 8.06-8.07 (2H, m), 8.19 (1H, s), 8.43-8.45 (1H, m)8.67 (1H, d, J=7.0 Hz), 10.05 (1H, s). m/z (ES⁺) 291 (MH⁺).

EXAMPLE 203-(3-Trifluoromethylphenyl)imidazo[1,2-a]pyridine-7-carboxaldehyde oxime

Hydroxylamine hydrochloride (24 mg, 0.34 mmol) was added to a stirredsuspension of3-(3-trifluoromethylphenyl)imidazo[1,2-a]pyridine-7-carboxaldehyde (91mg, 0.31 mmol) in ethanol (3 mL) at room temperature, causingdissolution. After 2 min, the pH was adjusted to 7 by addition oftriethylamine and the precipitated solid was collected by filtration,washed with ethanol and dried by a continuous stream of air, affordingthe title imidazopyridine as a white amorphous solid (60 mg, 63%). ¹HNMR (360 MHz, d₆-DMSO) δ 7.32 (1H, dd, J=7.2 and 1.8 Hz), 7.79-7.81 (3H,m), 7.95 (1H, s), 8.01-8.03 (2H, m), 8.25 (1H, s), 8.54 (1H, d, J=7.4Hz), 11.55 (1H, s). m/z (ES⁺) 306 (MH⁺).

EXAMPLE 213-(3-Trifluoromethylphenyl)imidazo[1,2-a]pyridine-7-carbonitrile

Trifluoroacetic acid anhydride (22 μL, 0.16 mmol) was added to a stirredsolution of3-(3-trifluoromethylphenyl)imidazo[1,2-a]pyridine-7-carboxamide (31 mg,0.10 mmol) in a mixture of pyridine (0.5 mL) and 1,4-dioxane (0.5 mL) at0° C. and the solution was allowed to warm to room temperature. After 2h, further trifluoroacetic acid anhydride (22 μL, 0.16 mmol) was addedand stirring was continued for 16 h. The solution was then concentratedin vacuo and partitioned between water (2 mL) and ethyl acetate (20 mL).The aqueous phase was extracted with further ethyl acetate (20 mL) andthe combined organic fractions dried over Na₂SO₄, filtered andconcentrated. The crude material was purified by column chromatographyon silica using 50% EtOAc in iso-hexanes to afford the desiredimidazopyridine (3 mg, 10%). ¹H NMR (360 MHz, d₆-DMSO) δ 7.29 (1H, dd,J=7.2 and 1.6 Hz), 7.80-7.87 (2H, m), 8.03-8.07 (2H, m), 8.19 (1H, s),8.48 (1H, s) 8.72 (1H, d, J=7.0 Hz). m/z (ES⁺) 287 (MH⁺).

EXAMPLE 227-(3-Chlorophenyl)-3-trifluoromethylimidazo[1,2-b][1,2,4]triazine

The title compound was made following the procedure of Example 1, Step 3using 7-bromo-3-trifluoromethylimidazo[1,2-b][1,2,4]triazine (3 g, 11.2mmol), 3-chlorobenzeneboronic acid (3.51 g, 22.5 mmol), 2N Na₂CO₃solution (22.5 mL), DME (40 mL) andtetrakis(triphenylphosphine)palladium(0) (650 mg, 0.6 mmol) to yield thetitle compound (1.11 g, 33%). ¹HNMR (400 MHz, CDCl₃): δ 7.45-7.52 (2H,m), 7.98 (1H, d, J=7.4 Hz), 8.16 (1H, s), 8.62 (1H, s), 8.88 (1H, s);m/z (ES+) 299, 301 ratio 3:1 (M+H⁺).

EXAMPLE 233-Trifluoromethyl-7-(3-trifluoromethylsulfanylphenyl)imidazo[1,2-b][1,2,4]triazine

The title compound was made following the procedure of Example 1, Step 3using 7-bromo-3-trifluoromethylimidazo[1,2-b][1,2,4]triazine (0.15 g,0.56 mmol),5,5-dimethyl-2-(3-trifluoromethylsulfanylphenyl)-[1,3,2]dioxaborinane(0.24 g, 0.84 mmol), 2N Na₂CO₃ solution (0.84 mL), DME (2 mL) andtetrakis(triphenylphosphine)palladium(0) (32 mg, 0.03 mmol) to yield thetitle compound (87 mg, 43%). ¹HNMR (400 MHz, CDCl₃): δ 7.64 (1H, t,J=7.9 Hz), 7.77 (1H, d, J=7.8 Hz), 8.21 (1H, d, J=7.8 Hz), 8.46 (1H, s),8.65 (1H, s), 8.86 (1H, s); m/z (ES+) 365 (M+H⁺).

EXAMPLE 247-[3-(1-Methyl-1H-[1,2,4]triazol-3-ylmethoxy)phenyl]-3-trifluoromethylimidazo[1,2-b][1,2,4]triazine

The reaction was carried out according to Example 1, Step 3 using7-bromo-3-trifluoromethylimidazo[1,2-b][1,2,4]triazine (0.1 g, 0.36mmol),3-[3-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)phenoxymethyl]-1-methyl-1H-[1,2,4]triazole(0.14 g, 0.45 mmol), 2N Na₂CO₃ solution (0.45 mL), DME (2 mL) andtetrakis(triphenylphosphine)palladium(0) (22 mg, 0.02 mmol) to yield thetitle compound (83 mg, 59%). ¹HNMR (400 MHz, CDCl₃): δ 3.95 (3H, s),5.25 (2H, s), 7.16-7.19 (1H, dd, J=8.2, 2.7 Hz), 7.48 (1H, t, J=8.1 Hz),7.71 (1H, d, J=7.8 Hz), 7.85-7.86 (1H, m), 8.06 (1H, s), 8.61 (1H, s),8.79 (1H, s); m/z (ES+) 376 (M+H⁺).

The following compounds can be made by analogous procedures to thosedisclosed in the foregoing Examples.

R₁ Z Me CHO Me

Me

CF₃ CF₃ Cl

Cl

V Z W H NO₂ F H NH₂ F H Br F H

F H

F H CH₂OCH₃ F H OCH₃ F H SCH₃ H H OCH₃ H H H F H N(CH₃)₂ H H Cl H H Br HH

H H COCH₃ H H

H H F H H F F H

F H CH(CH₃)₂ H H CH₃ H H CN F H CF₃ F H NO₂ H H CON(CH₃)₂ H H SO₂CH₃ H H

H H CF₂H H H SCF₃ H H SO₂N(CH₃)₂ H H CF₃ Cl H CF₃ CH₃ H

H H

H H

H F OCF₃ H F CN H H

H H

H H

H H

H H

H H

H H

H H OCH₂CN H H

H H

F H

F H

F Cl CF₃ H

V Z W H

F H CH₂Cl F H

F H

F H

F H

F H

F H

F H H F H

F H

F H OEt F H OCH₂CF₃ F H

F H

F H

F H OCH₂CN F H

H H

H H

F H

F H

F H

F H

F H

F H

F H O^(t)Pr F H

F H

F H

F H

F H

F H

F H

F H

F H

F H

F H

F H

F H

F H

F H

F H

F H

F H

F H

F H

F H

F H

F H

F H

F H OCH₂CF₂H F H O(CH₂)₂OMe F H O(CH₂)₂NMe F H

F H

F H

F H

F H

F H

F H CH₂OH F

1.-10. (canceled)
 11. A pharmaceutical composition comprising a compoundof formula I or a pharmaceutically acceptable salt thereof:

wherein: X and Y independently represent CH or N, with the proviso thatif X is CH then Y is also CH; R¹ represents hydrogen, hydrocarbon, aheterocyclic group, halogen, cyano, trifluoromethyl, nitro, —OR^(a),—SR^(a), —SOR^(a), —SO₂R^(a), —SO₂NR^(a)R^(b), —NR^(a)R^(b),—NR^(a)COR^(b), —NR^(a)CO₂R^(b), —COR^(a), —CO₂R^(a), —CONR^(a)R^(b) or—CR^(a)═NOR^(b); R^(a) and R^(b) independently represent hydrogen,hydrocarbon or a heterocyclic group; V and W are independently selectedfrom H, halogen, C₁₋₆alkyl, OH and C₁₋₆alkoxy; Z represents H, halogen,CN, NO₂, CF₃, OCF₃, CF₂H, SCF₃, R², OR³, SR³, (CH₂)_(p)N(R³)₂,O(CH₂)_(p)N(R³)₂, SO₂R², SO₂N(R³)₂, COR⁴, CO₂R³, CON(R³)₂, NHCOR⁴,NR′(CH₂)_(n)heteroaryl or O(CH₂)_(n)heteroaryl where the heteroaryl isoptionally substituted by one, two or three groups chosen fromC₁₋₆alkyl, benzyl, (CH₂)_(p)N(R³)₂, halogen and CF₃, R′ is C₁₋₆alkyl, nis 1 or 2 and p is 0, 1 or 2; with the proviso that at least one of V, Wand Z is other than H; R² represents C₁₋₆alkyl, C₃₋₆cycloalkyl,C₃₋₆cycloalkylC₁₋₄alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl or heteroaryl, any ofwhich may bear a substituent selected from halogen, CN, NO₂, CF₃, OCF₃,CF₂H, SCF₃, OH, C₁₋₄alkoxy, C₁₋₄alkoxycarbonyl, amino, C₁₋₄alkylamino,or di(C₁₋₄alkyl)amino; R³ represents H or R²; or two R³ groups bonded tothe same nitrogen atom may complete a 5-7 membered nonaromaticheterocyclic ring; and R⁴ represents R³ or heteroaryl; in apharmaceutically acceptable carrier.
 12. The pharmaceutical compositionof claim 11 wherein the compound of formula I: X and Y are CH.
 13. Thepharmaceutical composition of claim 11 wherein the compound of formulaI: X and Y are N.
 14. The pharmaceutical composition of claim 11 whereinthe compound of formula I: X is N and Y is CH.
 15. The pharmaceuticalcomposition of claim 11 wherein the compound of formula I is selectedfrom the group consisting of:3-(3-trifluoromethylphenyl)-7-trifluoromethylimidazo[1,2-a]pyrimidine;3-[3-cyanophenyl]-7-trifluoromethylimidazo[1,2-a]pyrimidine;7-{3-[(1,5-dimethyl-1H-pyrazol-4-yl)methoxy]-4-fluorophenyl}-3-trifluoromethylimidazo[1,2-b][1,2,4]triazine;3-(3-trifluoromethylphenyl)imidazo[1,2-a]pyridine-7-carboxamide;N-[2-fluoro-5-(3-trifluoromethylimidazo[1,2-b][1,2,4]triazin-7-yl)phenyl]-N-(3-pyridinylmethyl)amine;N-(1,5-dimethyl-1H-pyrazol-4-ylmethyl)-N-[2-fluoro-5-(3-trifluoromethylimidazo[1,2-b][1,2,4]triazin-7-yl)phenyl]amine;7-[4-fluoro-3-(1-methyl-5-trifluoromethyl-1H-pyrazol-4-ylmethoxy)phenyl]-3-trifluoromethylimidazo[1,2-b][1,2,4]triazine;3-[3-(1-methyl-1H-[1,2,4]triazol-3-ylmethoxy)phenyl]-7-trifluoromethylimidazo[1,2-a]pyrimidine;3-(2-fluoro-3-trifluoromethylphenyl)-7-trifluoromethylimidazo[1,2-a]pyrimidine;3-(3-trifluoromethoxyphenyl)-7-trifluoromethylimidazo[1,2-a]pyrimidine;or a pharmaceutically acceptable salt thereof.
 16. The pharmaceuticalcomposition of claim 11 wherein the compound of formula I is selectedfrom the group consisting of:7-(4-fluoro-3-methoxyphenyl-3-trifluoromethylimidazo[1,2-b][1,2,4]triazine;methyl 3-(3-trifluoromethylphenyl)imidazo[1,2-a]pyridine-7-carboxylate;N-[2-fluoro-5-(3-trifluoromethylimidazo[1,2-b][1,2,4]triazin-7-yl)phenyl]-N-methyl-N-(3-pyridinylmethyl)amine;7-[4-fluoro-3-(pyridin-2-ylethoxy)phenyl]-3-(trifluoromethyl)imidazo[1,2-b][1,2,4]triazine;2-fluoro-5-[3-(trifluoromethyl)imidazo[1,2-b][1,2,4]triazin-7-yl]benzaldehyde;3-(3-trifluoromethylphenyl)imidazo[1,2-a]pyrimidine;7-[3(1H-benzimidazol-2-ylmethoxy)-4-fluorophenyl]-3-trifluoromethylimidazo[1,2-b][1,2,4]triazine;.7-chloro-3-(3-trifluoromethylphenyl)imidazo[1,2-a]pyridine;3-(3-trifluoromethylphenyl)imidazo[1,2-a]pyridine-7-carboxaldehyde;3-(3-trifluoromethylphenyl)imidazo[1,2-a]pyridine-7-carboxaldehydeoxime; 3-(3-trifluoromethylphenyl)imidazo[1,2-a]pyridine-7-carbonitrile;7-(3-chlorophenyl)-3-trifluoromethylimidazo[1,2-b][1,2,4]triazine;3-trifluoromethyl-7-(3-trifluoromethylsulfanylphenyl)imidazo[1,2-b][1,2,4]triazine;7-[3-(1-methyl-1H-[1,2,4]triazol-3-ylmethoxy)phenyl]-3-trifluoromethylimidazo[1,2-b][1,2,4]triazine;or a pharmaceutically acceptable salt thereof.
 17. A method for treatingan individual suffering from diminished cognition which comprisesadministering to that individual a therapeutically effective amount of acompound of formula I or a pharmaceutically acceptable salt thereof:

wherein: X and Y independently represent CH or N, with the proviso thatif X is CH then Y is also CH; R¹ represents hydrogen, hydrocarbon, aheterocyclic group, halogen, cyano, trifluoromethyl, nitro, —OR^(a),—SR^(a), —SOR^(a), —SO₂R^(a), —SO₂NR^(a)R^(b), —NR^(a)R^(b),—NR^(a)COR^(b), —NR^(a)CO₂R^(b), —COR^(a), —CO₂R^(a), —CONR^(a)R^(b) or—CR^(a)═NOR^(b); R^(a) and R^(b) independently represent hydrogen,hydrocarbon or a heterocyclic group; V and W are independently selectedfrom H, halogen, C₁₋₆alkyl, OH and C₁₋₆alkoxy; Z represents H, halogen,CN, NO₂, CF₃, OCF₃, CF₂H, SCF₃, R², OR³, SR³, (CH₂)_(p)N(R³)₂,O(CH₂)_(p)N(R³)₂, SO₂R², SO₂N(R³)₂, COR⁴, CO₂R³, CON(R³)₂, NHCOR⁴,NR′(CH₂)_(n)heteroaryl or O(CH₂)_(n)heteroaryl where the heteroaryl isoptionally substituted by one, two or three groups chosen fromC₁₋₆alkyl, benzyl, (CH₂)_(p)N(R³)₂, halogen and CF₃, R′ is C₁₋₆alkyl, nis 1 or 2 and p is 0, 1 or 2; with the proviso that at least one of V, Wand Z is other than H; R² represents C₁₋₆alkyl, C₃₋₆cycloalkyl,C₃₋₆cycloalkylC₁₋₄alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl or heteroaryl, any ofwhich may bear a substituent selected from halogen, CN, NO₂, CF₃, OCF₃,CF₂H, SCF₃, OH, C₁₋₄alkoxy, C₁₋₄alkoxycarbonyl, amino, C₁₋₄alkylamino,or di(C₁₋₄alkyl)amino; R³ represents H or R²; or two R³ groups bonded tothe same nitrogen atom may complete a 5-7 membered nonaromaticheterocyclic ring; and R⁴ represents R³ or heteroaryl.
 18. The method ofclaim 17 wherein the individual is suffering from Alzheimer's Disease.19. The method of claim 17 wherein the compound of formula I: X and Yare CH.
 20. The method of claim 17 wherein the compound of formula I: Xand Y are N.
 21. The method of claim 17 wherein the compound of formulaI: X is N and Y is CH.
 22. The method of claim 17 wherein the compoundof formula I is selected from the group consisting of:3-(3-trifluoromethylphenyl)-7-trifluoromethylimidazo[1,2-a]pyrimidine;3-[3-cyanophenyl]-7-trifluoromethylimidazo[1,2-a]pyrimidine;7-{3-[(1,5-dimethyl-1H-pyrazol-4-yl)methoxy]-4-fluorophenyl}-3-trifluoromethylimidazo[1,2-b][1,2,4]triazine;3-(3-trifluoromethylphenyl)imidazo[1,2-a]pyridine-7-carboxamide;N-[2-fluoro-5-(3-trifluoromethylimidazo[1,2-b][1,2,4]triazin-7-yl)phenyl]-N-(3-pyridinylmethyl)amine;N-(1,5-dimethyl-1H-pyrazol-4-ylmethyl)-N-[2-fluoro-5-(3-trifluoromethylimidazo[1,2-b][1,2,4]triazin-7-yl)phenyl]amine;7-[4-fluoro-3-(1-methyl-5-trifluoromethyl-1H-pyrazol-4-ylmethoxy)phenyl]-3-trifluoromethylimidazo[1,2-b][1,2,4]triazine;3-[3-(1-methyl-1H-[1,2,4]triazol-3-ylmethoxy)phenyl]-7-trifluoromethylimidazo[1,2-a]pyrimidine;3-(2-fluoro-3-trifluoromethylphenyl)-7-trifluoromethylimidazo[1,2-a]pyrimidine;3-(3-trifluoromethoxyphenyl)-7-trifluoromethylimidazo[1,2-a]pyrimidine;or a pharmaceutically acceptable salt thereof.
 23. The method of claim17 wherein the compound of formula I is selected from the groupconsisting of:7-(4-fluoro-3-methoxyphenyl-3-trifluoromethylimidazo[1,2-b][1,2,4]triazine;methyl 3-(3-trifluoromethylphenyl)imidazo[1,2-a]pyridine-7-carboxylate;N-[2-fluoro-5-(3-trifluoromethylimidazo[1,2-b][1,2,4]triazin-7-yl)phenyl]-N-methyl-N-(3-pyridinylmethyl)amine;7-[4-fluoro-3-(pyridin-2-ylethoxy)phenyl]-3-(trifluoromethyl)imidazo[1,2-b][1,2,4]triazine;2-fluoro-5-[3-(trifluoromethyl)imidazo[1,2-b][1,2,4]triazin-7-yl]benzaldehyde;3-(3-trifluoromethylphenyl)imidazo[1,2-a]pyrimidine;7-[3(1H-benzimidazol-2-ylmethoxy)-4-fluorophenyl]-3-trifluoromethylimidazo[1,2-b][1,2,4]triazine;7-chloro-3-(3-trifluoromethylphenyl)imidazo[1,2-a]pyridine;3-(3-trifluoromethylphenyl)imidazo[1,2-a]pyridine-7-carboxaldehyde;3-(3-trifluoromethylphenyl)imidazo[1,2-a]pyridine-7-carboxaldehydeoxime; 3-(3-trifluoromethylphenyl)imidazo[1,2-a]pyridine-7-carbonitrile;7-(3-chlorophenyl)-3-trifluoromethylimidazo[1,2-b][1,2,4]triazine;3-trifluoromethyl-7-(3-trifluoromethylsulfanylphenyl)imidazo[1,2-b][1,2,4]triazine;7-[3-(1-methyl-1H-[1,2,4]triazol-3-ylmethoxy)phenyl]-3-trifluoromethylimidazo[1,2-b][1,2,4]triazine;or a pharmaceutically acceptable salt thereof.